ES2288631T3 - NEW BINDING PPAR THAT DOES NOT CAUSE FLUID RETENTION, EDEMA OR CONGESTIVE CARDIAC INSUFFICIENCY. - Google Patents

Abstract

Methods are provided for treating or prophylactically preventing metabolic disorders in humans without causing, promoting, or aggravating fluid retention, peripheral edema, pulmonary edema, or congestive heart failure, by administration of a therapeutically effective amount of a compound sufficient to partially or fully activate peroxisome proliferator activated receptors (PPARs) and partially or fully inhibit, antagonize or block the activity of angiotensin II type 1 receptors. Metabolic disorders that can be treated or prevented include but are not limited to type 2 diabetes, the metabolic syndrome, prediabetes, and other insulin resistance syndromes. Compounds are provided that antagonize or block the angiotensin 11 type 1 (AT1) receptor, function as partial or full activators of peroxisome proliferator activated receptors (PPARs), can be used to treat or prevent diseases blown to be treatable or preventable by PPAR activators and were not previously recognized to be therapeutic targets for angiotensin II receptor antagonists.

Description

New PPAR ligand that does not cause retention of fluids, edema or congestive heart failure.

Field of the Invention

This invention concerns the field of prevention of type 2 diabetes mellitus, metabolic syndrome and inflammation caused by osteoarthritis. Specifically, this invention concerns compounds that increase both the activity of receptors activated by peroxisomal proliferators (for the acronym of the English expression, Peroxisome proliferator activated receptors , PPARs *) and the blocking / antagonism activity of angiotensin II type receptors 1. More specifically, this invention concerns new clinical uses of certain angiotensin II type 1 receptor blockers (by the English acronym, Angiotesin Receptor Blockers , ARBs *) which may increase the activity of receptors activated by peroxisomal proliferators (PPARs).

Background of the invention

Peroxisomal proliferator-activated receptors (PPARs *) are members of the nuclear receptor superfamily of ligand-activated transcription factors. Three subtypes of PPARs have been cloned from the mouse and the human: that is, PPARα, PPARγ, and PPARβ. PPARs are important regulators of carbohydrate and lipid metabolism, cell growth and differentiation, phenotype transition, apoptosis, neovascularization, immunoregularization and inflammatory response. Compounds that activate PPARs are useful in the treatment and prevention of a variety of clinical disorders including, but not limited to metabolic syndrome, obesity, prediabetes, type 2 diabetes and other syndromes with insulin resistance, hypertension, atherosclerosis, dyslipidemia, inflammatory skin diseases such as psoriasis, inflammatory bowel disease and neurodegenerative inflammation diseases such as multiple sclerosis and Alzheimer's disease. The metabolic syndrome referred to in this application includes the metabolic syndrome as defined by either the World Health Organization (WHO) or the National Cholesterol Education Program (NCEP *) (Zimmet P, et al . Global and societal implications of the diabetes epidemic. Nature. (2001) 414: 782-7; Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation Diabet Med. (1998) 15: 539-53; Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III) JAMA (2001) 285: 2486-97).

Examples of known compounds that can activate PPARs include thiazolidinediones (eg rosiglitazone, pioglitazone, MK 767 (KRP-297), MCC-555, R-483, CS-011, NC2100, DRF-2189, PAT-5A, NIP-221, netoglitazone, balaglitazone, rivoglitazone) that primarily activate PPARgamma or PPAR gamma and PPAR alpha and non-thiazolidinediones that can activate any combination of PPAR gamma, PPAR alpha and PPAR delta (eg JTT-501, LSN862, DRF 4832 , LM 4156, LY 510929, LY 519818, TY 51501, X 334), some tyrosine based derivatives (eg GW1929, GW7845), phenylacetic acid based derivatives, phenoxazine phenyl propanoic acid based derivatives (eg DRF 2725, DRF 2189) cinnamic and dihydrocinamic acid-based derivatives (eg tesaglitazar (AZ 242) and 3-Fenyl-7-propylbenzisoxazoles (Adams AD, et al . Bioorg Med Chem Lett. (2003) 13: 931-5) , which can activate gamma PPARs in combination with PPAR alpha or PPAR delta, or both, PPAR alpha and PPAR delta. Compounds that can primarily activate PPAR alpha only or PPAR delta only, it is common that such compounds also cause at least some degree of activation of gamma PPARs.

Although some drugs that activate PPARs Gamma have proven useful for the prevention and treatment of Type 2 diabetes and a variety of other disorders, agents currently available cause adverse effects or aggravate certain disorders that may limit the clinical utility and safety of these ligands. Some of the main side effects limitations or disorders that can be caused or aggravated so much for thiazolidinedione compounds as for compounds without thiazolidinedione that activate gamma PPARs, either alone or in Combination with other PPARs are: fluid retention, edema peripheral, pulmonary edema and congestive heart failure. Both rosiglitazone and pioglitazone have received the regulatory approval for the treatment of type 2 diabetes in many countries including the United States and throughout the European Community. The vast experience accumulated with the use of These drugs internationally have shown that thiazolidinediones may cause fluid retention, which exacerbates or leads to edema and / or heart failure congestive (ICC). Patients with active edema are prone to adverse effects when under therapy with thiazolidinedione, and especially if combined with the insulin administration, consisting of up to 16% of patients of the last group. This is potentially a serious problem, considering that among patients with type 2 diabetes with the possibility of being treated with thiazolidinediones or others agonists without thiazolidinedione, a significant percentage have CHF or have a high risk of developing CHF due to their high cardiovascular risk profiles. Fluid retention caused by activators of PPARs, it can not only cause expansion of volume and peripheral edema, but can also induce or aggravate life-threatening diseases such as the ICC and the pulmonary edema. Therefore, there is considerable interest in identify and use the activators of gamma PPARs that do not cause substantial fluid retention and therefore not increase the risk of edema and / or heart failure congestive

The present invention relates to the surprising discovery that certain ARBs can increase the activity of PPAR gamma and can be used to treat or prevent type 2 diabetes, metabolic syndrome and other disorders that respond to the activators of the PPARs or to the activation of the PPARs, without raising the risk of fluid retention, edema peripheral, pulmonary edema or congestive heart failure. Although previous studies have shown that the risk for diabetes type 2 in patients who receive ARBs is lower than those of patients who are given other antihypertensive drugs, you could not have predicted that certain ARBs could be used to prevent or treat type 2 diabetes, the metabolic syndrome or other disorders susceptible to ligands PPARs

It has not been clear whether ARBs really decrease the risk of diabetes or if the drugs with which they were being compared increase the risk of diabetes. For example, the lower levels of diabetes risk reported in patients who are given ARBs versus beta blockers or thiazide diuretics were due to the fact that beta blockers and thiazide diuretics aggravate insulin resistance and by Therefore, the results of clinical studies when comparing ARBs with other agents cannot be used to predict whether ARBs can be used to prevent or treat diabetes or other disorders sensitive to gamma PPAR activators.

Several studies have investigated the effects of ARBs on glucose homeostasis, but the results are incompatible and controversial (for review on this subject see. Bemobich E, et al . Drugs (Drugs) (2002) 62: 1295-1314) . There are no data available that consistently demonstrate that ARBs increase insulin sensitivity, attenuate insulin resistance or that they can be used to treat or prevent type 2 diabetes, metabolic syndrome and other insulin resistance syndromes. . Expert opinions expressed in the medical and scientific literature maintain that drugs that block angiotensin II type 1 (ABs) receptors (also known as "frying pans" are "metabolically neutral" (Epstein M. Angiotensin II Receptor Antagonists Angiotensins : Current Status In: Angiotensin II Receptor Antagonists Epstein M and Brunner HR (eds), Hanley & Belfus, Inc., Philadelphia, (2002) pp 257-261) For example, the ARB losartan have a neutral effect on Glucose metabolism, insulin sensitivity and serum concentrations in patients with moderate hypertension (Bernobich E, et al . Drugs (2002) 62: 1295-1314) and in clinical studies with diabetic patients, candesartan does not alter appreciably his hemoglobin A1c, glucose concentration or lipid profile (Easthope SE, et al . Drugs 2002; 62: 1253-87).

In a recent clinical study ( IN VIVO study) where the ARB losartan was compared with the Atenolol Beta blocker, the incidence of new cases of type 2 diabetes was higher in patients treated with atenolol than in those treated with losartan (Dahlof B, et al Lancet (2002) 359: 995-1003). However, it is known that Beta-blockers such as atenolol are clinically diabetogenic and can cause or worsen insulin resistance and therefore stimulate the development of type 2 diabetes (Teuscher AU, et al . J Hypertens Suppl. (1997) 15: S67-75). Hence, the lower incidence of new cases of type 2 diabetes in the study group to which Losartan was administered, actually reflected an increase in the incidence of new type 2 diabetes debuts in the study group to which it was administered. Atenolol Studies that show a lower incidence of new diabetes debuts in patients treated with ARB candesartan do not decrease the risk of diabetes, rather, the thiazide diuretic increases the risk of diabetes. Therefore, the prior art could not be used to predict that losartan, telmisartan, irbesartan, or any other ARB could be used to prevent or treat type 2 diabetes, metabolic syndrome or other forms of insulin resistance. What's more, due to the important structural chemical differences that ARBs have, any unusual or unexpected results obtained with one of the ARBs cannot be used to predict that similar results would be obtained with another ARB.

In the obese rat Zucker , Henriksen et al . they found that oral administration of an extremely high dose of irbesartan improved insulin sensitivity but apparently could not improve lipid levels (Henriksen EJ et al . The antagonism of selective angiotensin II receptors reduces insulin resistance in Zucker obese rats. Hypertension. (2001) 38: 884-90). However, the obese rat Zucker is an unusual form of obesity and insulin resistance caused by mutations in the leptin receptor and in addition, those studied by Henriksen did not have type 2 diabetes. Mutations in leptin receptors in humans are extremely rare and almost never responsible for type 2 diabetes, obesity, insulin resistance or metabolic syndrome in humans. Therefore, studies by Henriksen et al ., In which it was found that an extremely high dose of irbesartan improves insulin sensitivity in obese Zucker rats, cannot be used to predict or imply that irbesartan or any other ARB could be used to activate PPARγ in vivo or be used to treat or prevent type 2 diabetes, metabolic syndrome or other insulin resistance syndromes in humans.

In 2002, after the present discovery was made, Sharma and his colleagues reported that very high concentrations of angiotensin II can inhibit the differentiation of human preadipocytes and that high concentrations of irbesartan can intensify adipogenesis (janke J, et al . Mature adipocytes inhibit in vitro the differentiation of human preadipocytes by type 1 angiotensin receptors. Diabetes. (2002) 51: 1699-707). Based on these findings and recent evidence showing that lack of adipose tissue can cause diabetes by causing excessive storage of fat in the muscle, liver, and pancreas (Danforth E, Jr. Does deficiency in adipocyte differentiation cause Type II diabetes mellitus - Nat Genet. (2000) 26:13), Sharma and colleagues proposed that blocking the renin-angiotensin system per se could prevent diabetes by stimulating adipocyte recruitment and differentiation (Sharma AM, et al . Angiotensin blockade prevents type 2 diabetes by the formation of fat cells Hypertension, (2002) 40: 609-11). In current studies, we have found that moderate concentrations of telmisartan and higher concentrations of irbesartan can activate PPARγ which is known to favor adipogenesis. Hence, blocking angiotensin receptors per se is not sufficient to favor increased activity of gamma PPARs or adipogenesis and is not sufficient to prevent or treat type 2 diabetes or any other resistance syndrome. insulin, including metabolic syndrome.

Given the number of clinical and experimental studies that suggest that angiotensin-converting enzyme (ACEI) inhibitors may improve insulin sensitivity and decrease the incidence of new type 2 diabetes debuts in patients with hypertension, it arises again. the question that if the pharmacological interruption of the renin-angiotensin system by other means, such as with angiotensin receptor blockers (ARBs), could also serve to predict that they are useful in the prevention or treatment of type 2 or other diabetes Insulin resistance syndromes (Yusuf S, et al . Ramipril and the development of diabetes. JAMA 2001: 286; 1882-5; Hansson L, et al . Effect of angiotesin-converting enzyme inhibition compared to therapy Conventional Cardiovascular Morbidity and Mortality in Hypertension: Randomized Study of the Prevention Project with Captopril (CAPPP *). (1999) 353: 611-6; Pri ncipales achievements in high-risk randomized hypertension patients treated with angiotensin-converting enzyme inhibitors or with calcium channel blockers versus diuretics: Study of antihypertensive and lipid-lowering therapy to prevent heart attack (ALLHAT *). JAMA (2002) 288: 2981-97; Bemobich E. et al . The role of the angiotensin system in cardiac homeostasis caused by glucose: therapeutic implications. Drugs (2002 62: 1295-314). However, recent studies have shown that the insulin sensitization effects of ACE inhibitors are related to their effects on quinine metabolism rather than their effects on the renin-angiotensin system (Tomiyama H, et al . Quinines contribute to the improvement of insulin sensitivity during treatment with the angiotensin-converting enzyme inhibitor Hypertension (1994) 23: 450-5; Shiuchi T, et al . ACE inhibitors improve insulin resistance in mice diabetics using bradykinin and NO. Hypertension. (2002) 40: 329-34; Bemobich E, et al . The role of the angiotensin system in cardiac glucose homeostasis: therapeutic implications. Drugs (2002) 62: 1295-314) . Hence, based on the results of studies using ACE inhibitors, it could not have been predicted that any of the existing ARBs would activate PPARγ and would be useful for preventing or treating type 2 dibes, metabolic syndrome or any Another insulin resistance syndrome.

Summary of the invention

Although we don't want to confine ourselves to the theory, drugs that activate gamma PPARs can cause fluid retention through a number of mechanisms. A amazing feature of this invention is that retention of fluids usually caused by drugs that activate PPARs gamma can be prevented or attenuated by blocking angiotensin II receptors, type 1. Product of the existence of multiple mechanisms that may be involved in retention of fluids caused by gamma PPARs ligands, could not have predicted that angiotensin receptor blockade could prevent or mitigate fluid retention caused by ligands Gamma PPARs in humans. Therefore, it could not have predicted that ARBs that activate PPARs could be used to prevent type 2 diabetes, or metabolic syndrome, without increasing the risk of fluid retention, edema or heart failure congestive

Until the present discovery described in the In this application, it was not known that certain ARBs could increase the activity of gamma PPARs. Hence, it could not have been predicted that certain ARBs could be used to prevent insulin resistance syndromes, type 2 diabetes, the metabolic syndrome or other known conditions are treatable through drugs that increase the activity of PPARs gamma

The present invention describes the surprising finding that there are and can develop drugs that block angiotensin II receptors, Type 1 (blockers of angiotensin receptors or ARBs) and which may also increase the activity of gamma PPARs. That is, there are some drugs that can work as both ARBs or as activators of PPARs Such agents include, but are not limited to, telmisartan and irbesartan and can be used to prevent type 2 diabetes, metabolic syndrome and other disorders that respond to the activation of gamma PPARs, including the inflammatory caused by osteoarthritis, without causing retention of fluids, edema or congestive heart failure. Hence the angiotensin receptor blockers such as the Telmisartan and Irbesartan can surprisingly be used to treat these states that are known to experts in the technique as sensitive to activators of gamma PPARs and can be used without causing fluid retention, edema or congestive heart failure

Because ARBs that increase activity of gamma PPARs do not cause substantial fluid retention and they do not increase the risk of edema and CHF, they represent a significant improvement with respect to drugs currently recognized that increase the activity of gamma PPARs. Be provide specific examples of ARBs that increase the activity of gamma PPARs in conjunction with a description of the novel clinical uses of these agents and instructions for the use of them. This invention also describes the fact of that new ARBs can be developed so that also increase the activity of gamma PPARs and alpha PPARs. These new ARBs will also be useful for preventing type 2 diabetes, the metabolic syndrome, without favoring fluid retention, peripheral edema, pulmonary edema or heart failure congestive

Because the compounds of this invention they also activate PPARs in addition to blocking the receiver of angiotensin II Type 1, said compounds provide more means effective in preventing inflammatory and metabolic disorders, including atherosclerosis, which compounds that block the angiotensin II Type 1 receptor but do not activate PPARs

Also surprisingly, when administering a ARB or ACE inhibitor before or in conjunction with compounds that activate gamma PPARs, either as pills, tablets or separate capsules or by administering both drugs formulated in a single pill, tablet or capsule, you can also prevent glucose intolerance or type 2 diabetes and other sensitivity disorders to PPARs without causing retention of fluids, edema or congestive heart failure.

This invention is about methods to prevent prophylactically an inflammatory or metabolic disorder in a mammal (human or non-human) without causing, causing or aggravating the fluid retention, peripheral edema, pulmonary edema or congestive heart failure, by administration to a mammal in need thereof, of a therapeutically amount effective of a compound sufficient to partially or completely activate receptors activated by peroximal proliferators (PPARs) and to, partially or totally, inhibit, antagonize or block the activity of angiotensin II type receptors one.

In one embodiment the mammal is a human, child, teenager or adult and therapeutically effective amount of the compound is used to prepare a drug for treatment of the metabolic disorder in the human.

In one embodiment, said compound increases PPAR subtype activity, gamma PPARs or heterodimers of retinoid X PPAR gamma receptors (PPARgamma-RXR), independently or in combination with an increase in activity of alpha PPARs, delta PPARs, or both, the PPARs alpha and the PPARs delta.

In one embodiment said compound is administered in a pharmacologically acceptable form and in an amount therapeutically effective enough to prevent prophylactically, slow down, delay the selected metabolic disorder or disease among the group consisting of insulin resistance, intolerance to glucose, deficiencies in glucose tolerance, fasting serum glucose deficiencies, deficiencies of the fasting blood glucose, hyperinsulinemia, prediabetes, diabetes type 1, diabetes mellitus type 2, hypertension due to resistance to insulin, metabolic syndrome, hypertension syndrome metabolic, syndrome X (metabolic), dismetabolic syndrome, obesity, visceral obesity, hypertriglyceridemia, concentrations elevated serum free fatty acids, concentrations high serum C-reactive protein levels high serum lipoproteins (a), high concentrations of homocysteine in serum, high concentrations of serum cholesterol produced by low lipoproteins density (LDL *), high concentrations of phospholipase associated with lipoproteins (A2), reduced cholesterol levels in the serum produced by high density lipoproteins (HDL *), reduced concentrations of serum cholesterol produced by HDL (2b), and reduced concentrations of adiponectin in the serum.

In a particular embodiment, as described in Pat. from EU No. 6 100 252 (Heterocyclic compounds and their use as angiotensin antagonists by Naka et al .) the compound has the following general formula:

one

In which R1 is a hydrocarbon residue optionally substituted, which is optionally linked to through a heteroatom; R2 is a heterocyclic residue of 5-7 members optionally subtitled, which has, as a group capable of constituting a ring, a carbonyl group, a thiocarbonyl group, an optionally oxidized sulfur atom, or a group that can become these; X is a direct link or a spacer that has an atomic length 2 or less between the ring Y and the ring W; W and Y are aromatic hydrocarbon residues optionally substituted containing a heteroatom or a residue optionally substituted heterocyclic; N is an integer of 1 or 2; a and b that form the heterocyclic residue are, so independent one or two carbons or heteroatoms optionally substituted; c is a carbon or a heteroatom optionally replaced; and, in the formula group:

2

the substituents of the two atoms adjacent that form the ring are optionally linked together to form a 5 or 6 member ring with the two atoms that they form the ring or a pharmaceutically acceptable salt thereof, or a solvate thereof pharmaceutically acceptable.

In one embodiment, the compound is formulated. For oral administration. In another embodiment, the compound is formulated for topical administration.

In a preferred embodiment, the compound is Telmisartan, or an analogue thereof. In another preferred embodiment,  the compound is irbesartan, or an analogue thereof. In some embodiments, the total daily effective dose administered orally is selected from an approximate range of 20 mg to 1000 mg.

The present invention also provides methods to examine compounds to prevent prophylactically inflammatory or metabolic disorders in a mammal through selection of a compound that has the properties of (a) so less partially activate the receptors activated by peroxisomal proliferators (PPARs); and (b) at least inhibit, antagonize or partially block a receptor activity of angitensin II type 1. In some embodiments the method It also includes the selection of a compound that does not cause, promote or aggravate fluid retention, peripheral edema, edema pulmonary or congestive heart failure in the mammal.

Detailed description of the invention

This invention concerns a method for prevent or delay metabolic syndrome or type 2 diabetes without cause systemic fluid retention, or increase the risk of fluid retention, peripheral edema, pulmonary edema or congestive heart failure by administering a compound that increases the activity of receptors activated by peroxisomal proliferadotes and blocks / antagonizes the activity of angiotensin II type 1 receptors. This invention also concerns novel clinical uses of certain blockers of angiotensin II type 1 receptors (ARBs) based on the discovery that the mentioned compounds can increase the proliferator activated receptor activity peroxisomal (PPARs), PPARγ, PPARα, or PPARδ, or any combination thereof and can be used to prevent diseases regulated by PPARs and their complications including metabolic or inflammatory diseases that were previously not considered therapeutic objectives of ARBs or more specifically of ARBs that do not activate PPARs. This invention also concerns methods for developing or using drugs that have the double capacity to block or inhibit system activity renin-angiotensin-aldosterone. Another aspect of this invention concerns methods for examining compound data banks to determine which ones are possible Candidates to practice this invention.

Definitions

The body mass index of a human patient is defined as the weight in kilograms divided by height in meters squared, so that the BMI has units of kg / m2.

Overweight is defined as the condition where the individual has a BMI greater than or equal to 25 kg / m2 and less than 30 kg / m2.

Obesity is defined as the condition where the individual has a BMI equal to or greater than 30 kg / m2. In another aspect, the term obesity is used to mean visceral obesity.

Visceral obesity is defined as a measure of the waist to hip of 1.0 in men and 0.8 in women, which in another aspect defines the risk of presenting insulin resistance and the development of prediabetes.

Euglycemia is defined as the condition in which a subject has a fasting blood glucose concentration within the normal range, greater than 70 mg / dl (3.89 mmol / L) and less than 110 mg / dl (6, 11 mmol / L). The word fasting has the usual meaning as a medical term.

Glucose tolerance deficiency (IGT) is defined as the condition in which a subject has a fasting blood glucose concentration or fasting serum glucose concentration greater than 110 mg / dl and less than 126 mg / dl (7.00 mmol / L) or a concentration of blood glucose or serum glucose 2 hours after eating food greater than 140 mg / dl (7.78 mmol / L) and less than 200 mg / dl (11 , 11 mmol / L). It is intended that the term glucose tolerance deficiency also refers to the fasting glucose deficit condition.

Hyperinsulinemia is defined as the condition in which a subject with insulin resistance, with or without euglycemia, in which the concentration of serum glucose or plasma insulin fasting or after eating food, is elevated above Normally, it causes lean individuals without insulin resistance to have a waist to hip measurement <1.0 (for men) or <0.8 (for women).

The terms " insulin sensitization ", " improvement of insulin resistance " or " decrease in insulin resistance " are synonymous and are used interchangeably.

Insulin resistance is defined as a state in which the levels of circulating insulin in excess of the normal response to a glucose load have to maintain the euglycemic state (Ford ES, et al . JAMA. (2002) 287: 356- 9). The insulin resistance index and the response to therapy of a patient with insulin resistance can be quantified by evaluating the results of the homeostasis assessment model for insulin resistance (HOMA-IR), a reliable indicator of insulin resistance. (Katsuki A, et al . Diabetes Care 2001; 24: 362-5). The estimated value of insulin resistance through the results of the model assessment (HOMA) -IR is calculated using the formula (Galvin P, et al . Diabet Med 1992; 9: 921-8):

HOMA-IR = [fasting seroglucose (µU / mL] x [fasting plasma glucose (mmol / L) / 22.5]

Patients with predisposition for developing IGT or type 2 diabetes are those that present euglicemia with hyperinsulinemia and are by definition resistant to insulin. A typical patient with insulin resistance suffers Usually overweight or obese.

The term prediabetes is the condition in which an individual is predisposed to the development of type2 diabetes. Prediabetes extends the definition of glucose tolerance deficiency to include individuals with fasting blood glucose levels within the normal high range ≥100 mg / dL (JB Meigs, et al . Diabetes 2003; 52: 1475- 1484) and hyperinsulinemia (high plasma insulin levels). The scientific and medical basis for identifying prediabetes as a serious threat to health is set out in a Position Statement entitled "The Prevention or Delay of Type 2 Diabetes" jointly published by the Association American Diabetes and the National Institute of Diabetes and Digestive and Nephrological Diseases (Diabetes Care 2002; 25: 742-749).

Individuals prone to being insulin resistant are those that have two or more of the following features: 1) overweight or obesity, 2) high blood pressure, 3) hyperlipidemia, 4) one or more first-degree diagnoses of IGT or type 2 diabetes. Insulin resistance can be confirmed in these individuals when calculating the results of HOMA-IR. For the purposes of this invention, the Insulin resistance is defined as the clinical condition in the which individual has a HOMA-IR result> 4.0 or a HOMA-IR result above the limit upper normal as defined by the laboratory performing the tests of glucose and insulin.

Type 2 diabetes is defined as the disease in which a subject has a fasting blood glucose or seroglucose concentration greater than 125 mg / dL (6.94 mmol / L).

Metabolic syndrome , also called syndrome X (when used in the context of metabolic disorders), also called dysmetabolic syndrome , is a complex syndrome whose fundamental characteristic is insulin resistance (Laaksonen DE, et al . Am J Epidemiol 2002; 1561070-7). According to ATP III guideline NCEP (Executive Summary of the Third Report of the National Program for Cholesterol Education (NCEP *) Panel III) Panel of experts in Detection, Evaluation and Treatment of high concentrations of blood cholesterol (Treatment of Adults Panel III ) JAMA: Journal of the American Medical Association (2001) 285: 2486-2497), the diagnosis of metabolic syndrome is made when 3 or more of the following risk factors are present:

one.

Abdominal obesity, defined as waist circumference> 40 inches or 102 cm in men and > 35 inches or 94 cm in women.

2.

Triglycerides: ≥ 150 mg / dL

3.

HDL-cholesterol <40 mg / dL in men

Four.

Blood pressure ≥ 130/85 mm Hg (SBP? 130 or DBP? 85)

5.

Fasting blood glucose ≥ 110 mg / dL

The NCEP definitions have been validated (Laaksonen DE, et al . Am J Epidemiol. (2002) 156: 1070-7).

The term congestive heart failure (CHF) includes heart failure of any etiology, including but not limited to heart failure with diastolic dysfunction, heart failure with systolic dysfunction, heart failure associated with cardiac hypertrophy and heart failure that develops as a result of myocarditis Infectious, inflammatory myocarditis, chemical myocarditis, heart disease of any etiology, hypertrophic heart disease, congenital heart disease and heart disease associated with ischemic heart disease or myocardial infarction.

The term PPAR refers to one or any combination of PPARalfa, PPARgamma and PPARdelta.

The term PPAR gamma refers to one or any combination of PPARgamma1, PPARgamma2, PPARgamma3.

The terms PPAR activator or PPAR gamma activator refer to any compound that, by any mechanism , increases or causes an increase in the activity of gamma PPARs or of gamma PPARs heterodimers with retinoid X receptors (RXR) , either by direct linkage with gamma or RXR PPARs, or indirectly through any other mechanism that affects the ability of gamma PPAR or PPARgamma-RXR heterodimer to influence genetic expression. These PPAR activators can affect the activity of the gamma PPARs either alone or in combination with the activation of other PPARs including the PPAR alpha or the PPAR delta or both, the PPAR alpha and the PPAR delta.

A PPAR-dependent disease is a disease in which 1) the administration of a PPAR ligand slows, improves, stops or reverses the pathological process and / or 2) said disease is associated with a deterioration in the transduction of ascending signals from a PPAR and its interaction with the gene transcription machinery, and / or 3) activation, partial activation or antagonism by a PPAR ligand (PPAR?, PPAR?, PPAR?) Leads to prevention, improvement, cure or arrest of the mentioned disease or pathological process.

An angiotensin II-dependent disease is a disease in which: 1) the administration of an AT1 receptor antagonist slows, improves, stops or reverses the pathological process and / or 2) the said disease is associated with a deterioration in transduction of signals within the RASS system and / or 3) said disease is facilitated or exacerbated by activation of the AT1 receptor by means of angiotensin II, the initial step being the resulting link of angiotensin II and the AT1 receptor. Because angiotensin II is a pro-inflammatory mediator, angiotensin II-dependent diseases are assumed to be inflammatory in nature (Phillips MI, Kagiyama S. Curr Opin Investig Drugs 2002; 3: 569-77). ARBs have the potential to improve inflammatory diseases, and since PPARs ligands also function as anti-inflammatory agents with different mechanisms of action, ARBs / PPARs double ligands will have novel and more potent synergistic effects on inflammatory diseases (Tham DM, et al. Physiol Genomics 2002; 11: 21-30).

An inflammatory disease is a disease associated with a dysfunction of the immune system, exemplified as but not limited to: 1) elevated production of inflammatory cytokines (interleukin (IL) -1 beta, IL-2, IL-6, IL-8, IL -12, tumor necrosis factor-?, Interferon-?, Monolith chemoattractant protein-1), 2) increased conversion of Th2 lymphocytes to Th1 phenotype or increased Th1 / Th2 ratio, 3) improper functioning of NK lymphocytes (killer: killers) T resulting in autoantibodies and lack of "self" recognition resulting in an autoimmune disease, 4) increased expression or activation of inflammatory nuclear transcription factors (NFAT, NF-? AP, 1 , JNK / STAT), 5) increased expressions of INOS.

A proliferative disease is a disease associated with: 1) pathological proliferation of normally quiescent cells, 2) pathological migration of cells from their normal location (for example metastasis of neoplastic cells), 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases cellular (collagenases, gelatinases, elastases), 4) pathological angiogenesis such as proliferative retinopathy and tumor metastasis.

Angiogenesis is the process by which the normally quiescent endothelium responds to physiological or pathological stimuli (such as proliferative endometrium, injury, tumor growth or diabetic retinopathy) that causes a pathological proliferation of blood vessels (neovascularization). Pathological angiogenesis (neovascularization) is an unregulated and uncontrolled process that results in inappropriate vascular proliferation such as neovascularization tumor, lymphangiogenesis and tumor metastasis.

A degenerative disease is a disease associated with the deterioration or destruction of normal tissue as a result of a deregulation of the immune system causing increased regulation of one or more inflammatory factors of nuclear transcription, inflammatory cytokines and other inflammatory molecules such as proteases (example MMP-9 ) and INOS, causing the pathological degeneration of the respective cell, tissue or organ object of the therapy.

The term heart failure includes congestive heart failure, heart failure with diastolic dysfunction, heart failure with systolic dysfunction, heart failure associated with cardiac hypertrophy and heart failure that develops as a result of chemically induced heart disease, congenital cardiomyopathy and disease-associated cardiomyopathy Ischemic or myocardial infarction.

The present invention relates to the surprising discovery that certain ARBs can also act as activators of gamma PPARs and can be used to prevent, delay, slow down, stop metabolic syndrome or diabetes type 2, as well as other disorders sensitive to activators of PPARs without increasing the risk of fluid retention, edema peripheral, pulmonary edema or congestive heart failure. From hence the present invention provides novel uses for certain ARBs for the prevention of diseases known as sensitive to drugs that increase the activity of gamma PPARs, including metabolic or inflammatory diseases. By consequently, the present invention is about the discovery of how to produce, identify and use drugs that activate PPARs gamma and that do not increase the risk of fluid retention, edema or congestive heart failure such as existing drugs that activate gamma PPARs. This invention relates to discovery that it is possible to produce and use compounds that they have the double ability to block or inhibit the system renin-angiotensin-aldosterone and the ability to activate gamma PPARs. The invention provides specific examples of such compounds that had not been previously recognized as having this double ability and shows that these compounds can be used to treat disorders of which it was not previously known that they were sensitive to such compounds. Therefore, this invention is about the surprising discovery that one can use certain drugs to treat disorders sensitive to the treatment of activators of PPARs.

The present invention provides novel uses for ARBs that also activate PPARs for the prevention of diseases that are known as sensitive to PPARs ligands, in particular to partial agonists of gamma PPARs or Total agonists of gamma PPARs. The diseases object of treatment include metabolic diseases and inflammatory The present invention also deals with the identification of new or previously unknown ARBs that they can also activate gamma PPARs and have a propensity reduced to cause fluid retention, edema or insufficiency congestive heart compared to other activators of PPARs gamma Therefore the present invention relates to discovery of how to identify the compounds that block the renin-angiotensin system and at the same time activate gamma PPARs but have a significant risk less causing fluid retention, edema or heart failure congestive The invention provides specific examples of ARBs. that had not previously been recognized as sensitive to said compounds. Therefore, this invention is about the surprising discovery that certain ARBs can be used for the purpose of treating or preventing disorders sensitive to treatment with PPARs ligands, said ligands having an increase in Safety and therapeutic efficacy.

This invention relates to the unpredictable and surprising discovery that certain compounds can block the renin-angiotensin system antagonizing AT1 receptors while activating PPARs, in particularly the PPARgamma.

In another aspect the invention is about Novel clinical uses of ARBs in the prevention of disorders  or diseases sensitive to PPARs.

In another aspect this invention is about novel clinical uses of ARBs in the prevention of diseases and disorders in which regulation is involved dependent on PPARs or interaction with receptors related nuclear devices that include the retinoid X receptor (RXR *), Orphan Retinoid Receptors (ROR *), the liver X receptor (LXR *), the farnesoid X receptor (FXR *) the vitamin receptor D (RVD *), estrogen receptors (ER * -alpha and ER-beta), glucocorticoid receptors (GR *), thyroid receptors (TR *), and the androgen receptor (AR *).

In another aspect this invention is about the study and identification of those ARBs that regulate the activity of PPARs, thus providing more therapeutic efficacy. safe and high to prevent diseases or disorders in the ARBs or organ complications are involved Terminals of these diseases.

In another aspect, this invention is about the identification of low toxicity PPAR ligands that are effective inhibitors of ARBs or RCTs by discrimination through evidence of liaison with the receiver AT1.

In another aspect, this invention is about methods to identify the ARBs or derivatives thereof, which may be made to further increase your ability to activate PPARs and to treat diseases sensitive to PPARs or the diseases, disorders or conditions in which the PPARs more effectively.

The compounds described herein request have renoprotective effects and are more effective for the treatment of kidney diseases or to limit the speed of progression of kidney diseases (by example, glomerular nephritis, glomerulosclerosis, syndrome Nephrotic, hypertensive nephrosclerosis, diseases polycystic kidneys and diabetic nephropathy) compared with compounds that do not possess this double ability to inhibit system activity renin-angiotensin-aldosterone and to activate the PPARs.

A compound or pharmaceutical composition as described in the present application, has the effect of reducing the blood sugar level, the effect of reducing lipids in blood, the effect of reducing blood insulin, the effect of increase insulin sensitivity, the effect of improving insulin resistance, the effect of reducing body weight, the effect of decreasing the central circumference of the body (measure hip-waist ratio), the effect of reduce fat body mass through the effects of activity of gamma PPARs, PPARgamma-RXR or through effects of related nuclear receptors, including FXR, LXR, ROR, the fixative protein of the CAMP response element (CREB *), CREB binding protein (CBP), CBP / p300, sterol regulatory binding proteins (SREBPs *), the Steroid receptor coactivator-1 (SRC-1), the coactivator-1 of the PPARs gamma (PGC-1alpha), the coactivator-1beta of gamma PPARs (PGC-1beta) and the PPARs binding protein (PBP *).

While the dose of a compound or composition pharmaceutical varies, depending on several factors such as the subject to be treated, the route of administration, the disease or disorder to be treated, a compound according to the present invention as an active ingredient can, for example, be administered to a human orally in a daily dose of around from 0.05 to 100 mg / kg body weight, preferably around from 0.1 to 10 mg / kg body weight, preferably from one to three times a day, preferring a single dose that provides therapeutic efficacy for at least 24 hours.

A compound as described herein. request has the effect of reducing blood sugar level, the effect of reducing blood lipids, the effect of reducing blood insulin, the effect of increasing sensitivity to insulin, the effect of improving insulin resistance, the effect of reducing body weight, the effect of reducing central circumference of the body (measured as a proportion waist-hip), the effect of reducing mass lipid of the body through the activity of PPARs dependent on ligands or receptor function activities nuclear related to PPARs. A PPAR is a factor of nuclear transcription, and the term is used here to cover nuclear receptors of PPARγ, PPARa, PPARb which they function as transcription factors of DNA bonds, which they have as a secondary modulator ligand for a nuclear receptor associated dimeric, such as a fat-soluble vitamin (vitamin A, vitamin D), a retinoid or steroid hormone, and maybe any monomer receptor, homodimer receptor and heterodimer receptor. A homodimer receptor is exemplified through the retinoid receptor Or (hereafter occasionally abbreviated as ROR? (GenBank Accession No.L14611) RORB (GenBank Accession No.L14160), RORγ (GenBank Accession No.U16997); Rev-erb \ alpha (GenBank Accession No.M24898), Rev-erb? (GenBank Accession .L31785); ERR α. (GenBank Accession No.X51416), ERR? (GenBank Accession No.X51417); Ftz-Fl ?. (GanBank Accession No. S65876), Ftz-Flα. (GenBank Accession No.M81385); Tlx (GenBank Accession No. S77482); GCNF (GenBank Accession No.U14666) and others similar. A receiver homodimer may, for example be a homodimer formed from a retinoid X receptor (hereinafter abbreviated occasionally as RXRα) (GenBank Accession No. X52773), RXRγ. (GenBank Accession No.M84820), RXRy (GenBank Accession No.U38480); COUP? (GenBank Accession No.X12795), COUP? (GenBank Accession No.M64497), COUP γ (GenBank Accession No.X12794); TR2? (GenBank Accession No.M29960), TR2? (GenBank Accession No.L27586); or, HNF4? (GenBank Accession No.X76930), HNF4γ. (GenBank Accession No.Z49S26) and others by the style. A heterodimeric receptor may, for example, be a heterodimer formed from a retinoid receptor X (RXR?, RXR? Or RXR?) Described above in conjunction with a receiver selected from a composite group by a retinoid A receptor (hereinafter abbreviated occasionally as RAR? (GenBank Accession No.X06614), RAM? (GenBank Accession No.Y00291), RAR? (GenBank Accession No. M24857); a thyroid hormone receptor (now hereinafter abbreviated occasionally as TRα (GenBank Accession No.M24748), TRβ (GenBank Accession No.M26747); a Vitamin D receptor (VDR) (GenBank Accession No. J03258); a peroxisome proliferator activated receptor (hereafter forward occasionally abbreviated as PPAR? (GenBank Accession No.L02932), PPAR \ beta (PPARdelta) (GenBank Accession No.U10375), PPARγ (GenBank Accession No.L40904); LXRα (GenBank Accession No.U22662), LXR? (GenBank Accession No.U14534); FXR (Gen-Bank Accession No. U18374); MB67 (GenBank Accession No.L29263); ONR (GenBank Accession No.X75163; and NURα. (GenBank Accession No.L13740), NUR. \beta. (GenBank Accession No.X75918), NUR. γ. (GenBank Accession No.U12767).

The present invention originates from surprising discovery that certain ARBs can activate the PPARγ, promote adipogenesis, decrease resistance to insulin and can be used to prevent metabolic syndrome and the components of this (see definitions) and type 2 diabetes. Among the ARBs currently approved for human consumption are they find "telmisartan" and "irbesartan" as specific examples of such compounds and may surprisingly be used to treat or prevent insulin resistance, the metabolic syndrome and type 2 diabetes (for example, for decrease hyperinsulinemia and / or hyperglycemia), the low level of triglycerides, and the high level of cholesterol produced by the HDL. An extension of this invention consists in the design predictive of derivatives of existing ARBs to improve the Insulin resistance decrease activity through the EC50 increase for PPARγ activation.

It has been previously shown that the risk of diabetes in patients who are given ARBs is lower than that of patients who are given other antihypertensive drugs. However, until the present discovery described in the present application, it was not known that these drugs could activate PPARγ and it could not have been predicted that these drugs could be used to treat insulin resistance syndromes, such as diabetes. Type 2 or other disorders that are known are treatable by PPARs ligands. For example, the lower risk of diabetes reported in patients who were given ARBs versus ? -Blockers (Dahlof B, et al . Lancet 2002; 359: 995-1003) could have been due to the fact that? Blockers aggravate insulin resistance and therefore, the results of clinical studies comparing ARBs with other agents cannot be used to predict whether ARBs can be used to treat diabetes or other disorders sensitive to PPARγ ligands.

Because ARBs do not cause retention of substantial fluids and do not increase the risk of edema or heart failure, they represent a significant improvement with respect to PPARs ligands that are currently recognized. Be provide specific examples of ARBs that activate PPARγ in conjunction with a description of novel clinical uses of these agents and instructions for their use. This invention is also about the novel discovery that they can derive new ARBs with greater ability to activate the PPARs than existing ARBs, and that said ARBs that have a Increased ability to activate PPARs can be used to prevent or treat clinical disorders known as sensitive to PPARs ligands without causing the degree or extent of effects side effects of fluid retention, edema or heart failure congestive caused by the PPARs ligands that are traded currently. Surprisingly, modifications can be made to the ARBs currently available that significantly increase the their ability to activate PPARs and therefore increase the their ability to treat disorders known as sensitive to PPARs ligands. Such compounds also they represent an improvement over existing ARBs since they have greater ability to activate PPARS and therefore, they have the additional benefits of improving disorders clinicians who are sensitive to treatment with activators of PPARs By using the methods described in this application, you can identify, develop and use PPAR ligands that have the ability to inhibit the activity of ACEIs or angiotensin receptor blockers. Such compounds they represent a novel approach to treat known disorders as sensitive to PPARs ligands because they do not favor fluid retention, edema or heart failure cogestive to the extent that it is known that current PPAR ligands available.

Specific examples of ARBs are provided which activate PPARγ in conjunction with a description of Novel clinical uses of these agents and instructions for use thereof. This invention is also about the discovery novel that new ARBs can be derived with greater skill to activate PPARs than existing ARBs and of which such ARBs, by having a greater ability to activate PPARs, they can be used to prevent or treat known clinical disorders as sensitive to PPARs ligands without causing the degree or extent of side effects of fluid retention, edema or congestive heart failure caused by ligands PPARγ that are currently on the market. Surprisingly, the ARBs can be structurally modified currently available in the market to increase significantly their ability to treat disorders that They are known to be sensitive to PPARs ligands. Such compounds they also represent an improvement over existing ARBs by activating PPARs more efficiently and therefore, they have the additional benefits of improving clinical disorders that are sensitive to treatment with PPAR activators. When using The methods described in this application can be identify, develop and use PPARs ligands that have the ability to antagonize AT1 receptors. Such compounds they represent a novel approach to treat disorders that are know they are sensitive to PPARs ligands since they do not favor the fluid retention, edema or congestive heart failure in the extent to which it is known do the available PPAR ligands currently. Although we don't want to oppose the theory, PPARγ ligands cause fluid retention by a number of mechanisms. An amazing feature of this invention is that fluid retention usually caused by ligands PPARγ can be prevented or attenuated by blocking the AT1 receptors. Because the blocking of the AT1 receiver is not always attenuates or prevents fluid retention in some animals models treated with PPARγ ligands and because Multiple mechanisms can be involved in retaining fluids caused by PPARγ ligands, could not be predicted that blocking AT1 receptors could prevent or mitigate fluid retention caused by PPARγ ligands in humans. Also surprisingly, when administering an ARB before or simultaneously with the compounds that activate PPARgamma either in the form of separate pills or tablets or by administration of both drugs formulated in a pill or tablet unique, you can also treat glucose intolerance or type 2 diabetes and other disorders that are sensitive to PPARs without causing fluid retention, edema or congestive heart failure.

Because PPARγ is not recognized as structurally related to the AT1 receptor, it would not be expected that the ARBs will activate the PPARγ. Hence, I could not had predicted that any existing ARB could be used to activate the PPARγ. Therefore, it could not be predicted that ARBs would be useful for treating ligand sensitive disorders PPARγ or that drugs that have the ability to block the AT1 receiver and they have in turn the ability to activate PPARγ. This invention is about surprising discovery that compounds can develop to antagonize the AT1 receptor while also they have the ability to activate PPARγ, and on the discovery that such compounds can be surprisingly useful for treating known disorders are sensitive to PPARγ ligands without promoting fluid retention, edema or heart failure. Also surprisingly, when administering an ARB that also activates PPARγ, the insulin resistance, metabolic syndrome, intolerance to glucose, type 2 diabetes, ovarian syndrome polycystic, as well as other disorders sensitive to PPARγ without causing fluid retention, edema or heart failure congestive These findings suggested that, like the thiazolidinedione antidiabetic PPARγ agonists, the Telmisartan can also increase insulin resistance. We determined that the administration of telmisartan to a patient with the metabolic syndrome increases insulin resistance according to It is determined by the reduction of the HOMAIR index (see definitions). To the administer telmisartan to a patient with type 2 diabetes, hyperglycemia decreased, triglycerides decreased plasma, and blood cholesterol levels were raised by HDL. These findings led to the surprising discovery and invention that ARBs that also activate PPARγ are useful for preventing and treating metabolic syndrome, diabetes type 2, and increase lipid metabolism by decreasing triglycerides and raising HDL cholesterol. These Antidiabetic and insulin sensitizing effects are limited to certain ARBs, such as telmisartan and irbesartan. ARBs such as valsartan and eprosartan, which do not activate the PPARγ in doses reasonably obtainable in doses therapeutic, did not favor adipogenesis, a property of Telmisartan and PPARγ thiazolidinediones agonists that sensitize insulin. Therefore, the ownership of reduce insulin resistance is restricted to the class of Non-peptide ARBs known as "frying pans" and are surprisingly unpredictable and not obvious. This invention is refers to methods to determine which "pans" or other AT1 receptor antagonists can function as agents Insulin sensitizers, resistance enhancers insulin or antidiabetics.

The insulin resistant states predispose to diseases, proliferative and degenerative such  such as atherosclerosis, atherogenesis, vascular stenosis or restenosis after invasive intravascular procedures, Cardiomyopathy and myocardial fibrosis. What's more, excessive use of glucocorticoids and / or immunosuppressive agents, such as those used in the treatment of chronic inflammatory diseases and Immunosuppression complications in homograft rejection, such as osteoporosis, Cushing's disease, lipodystrophy,  insulin resistance, type 2 diabetes, hyperlipidemia, transplant-associated hypertension, atherosclerosis, kidney diseases, arteritis and endarteritis. This invention predicts that the administration of an ARB that also activates PPARγ would result in a clinical improvement of these disorders.

Uses of the invention

The uses provided by this invention are practice by administering to a human or a vertebrate animal that needs a dose of a compound, or a salt, ester, solvate or tautomer thereof, acceptable pharmaceutically, which blocks or antagonizes the receptor of angiotensin II type 1 and active, either to PPARgamma alone or in combination with PPARalfa, or PPARdelta both PPARalfa and PPARgamma. In another aspect, the novel compounds used for Practicing this invention are described above. The specific diseases and associated disorders that may be treated with the compounds described in the present application, they are related in Tables I to X.

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22

The oral route of administration is the mode Preferred to prevent type 2 diabetes, metabolic syndrome and most other chronic disorders. The agents Therapeutics are administered topically to treat disorders that include the eyes or skin, except in some cases in which oral administration is preferred. In addition, the agents can be applied, administered parenterally, especially to treat retinitis and retinal diseases degenerative, as well as for other disorders in which it is not Possible oral or topical therapy. Parenteral therapy is typically oral, intraocular, transcutaneous, intradermal, intrathecal, intramuscular, joint, by inhalation, intravascular, sublingual, by suppository (for example, by rectum or by vaginal application), or by another parenteral route.

A preferred way to practice the methods described in the present application for dermatological disorders or ophthalmic that appear in Tables I to X to which You can apply this method, is to apply the compound of interest, in a cream, lotion, ointment or oil based carrier, directly in the injury. Typically, the concentration of Therapeutic compound in a cream, lotion or oil is 0.1 up to 2.5% In general, the preferred route of administration is oral, topical, intraocular or parenteral. Administration is preferred topical in the treatment of skin lesions, such as psoriasis, external eyepieces, such as conjunctivitis, keratitis, scleritis, squamous cell carcinoma, corneal erosion, syndrome of the dry eye, or the anterior chamber of the eye, such as glaucoma, the uveitis or other diseases of the uveal tract, in which the referred direct application is indicated practice and clinically

Oral administration is preferred as alternative treatment for the treatment of other injuries related in Tables I to X, in which the Direct topical application is not useful as it is in treatment of acute chronic or systemic diseases and diseases of the posterior segment of the eye, as in retinitis and others degenerative retinal diseases. The administration intravascular (the preferred route being intravenous) may be necessary in disorders that cannot be treated effectively by topical or oral administration.

Intraocular, transcutaneous injections, intradermal, intrathecal, intramuscular, articular or other invasive techniques are preferred alternatives in cases where which the doctor wishes to treat one or some specific areas or lesions, depending on the location of these in the eye. Usually, the compound is administered in an aqueous solution. In addition, the therapeutic compounds are injected directly into lesions (administration in injury) in appropriate cases. The intradermal administration is an alternative for injuries extraocular Injections in lesions and intradermal are routes application alternatives for certain injuries, for example, extraocular or hyperplastic neoplastic lesions such as the squamous cell carcinoma and condyloma respectively. The Inhalation therapy is preferable in diseases pulmonary, the sublingual suppository or in the rectorectal is preferable for rapid administration or in clinical situations in which the oral or intravascular route is inconvenient or problematic Application by vaginal topical formulation or suppository formulation is preferable for diseases  located in the vagina or other segment of the urogenital tract.

An effective amount of the compound is used in The treatment of interest. The dose of the compounds used according to the invention varies depending on the compound and the disorder that It is being treated. For example, age, weight and clinical status of the receiving patient, and the experience and evaluation of the clinician or Practical doctor who administers the therapy are among the factors involved in the selected dose. Other factors include: the route of administration, the patient, the medical history of the patient, the severity of the disease process, and the potency of the particular compound. The dose should be sufficient. to improve the symptoms or signs of the disease treated without produce an unacceptable toxicity to the patient.

In general, an effective amount of the compound is the amount that provides either a subjective relief of the symptoms or (continued) objective improvement that can be identified by the clinician or other qualified observer. The typical oral dose It is between 1 mg daily up to 1000 mg daily, at the doctor's discretion. Typically, the daily dose of the compounds of this invention it will depend on their ability to activate gamma PPARs and its ability to block the angiotensin II type 1 receptor. The doses of these compounds will generally fluctuate between 0.1 mg. up to 1000 mg daily, the common dose being 5 mg daily up to 300 mg daily Typically, the greater the ability to activate gamma PPARs and block angiotensin receptor II, the more effective the compound, and the lower the dose that is Consider an effective amount.

A tabulated oral dose is typically a dose. Only once a day. However, more than one can be administered dose per day. Due to the low incidence of side effects no desired, the compounds of this invention can be administered until an improvement in the disorder of interest is observed, and may be maintained as required to maintain such improvement of clinical status The compounds may or may not be administered. with food or with other agents depending on how they affect the food or other agents absorbing them by the body and depending on the assessment of experts in the therapeutic technique

The dose can be administered once or twice. a day, but the clinician may recommend more or less doses frequent. Once a therapeutic result has been obtained, the administration of the compound can be adjusted, continued or discontinued according to the doctor's recommendation. Occasionally, the side effects justify the discontinuation of the therapy.

An effective amount is used in the treatment of the compound of interest. The dose of the compounds used according to the invention varies depending on the compound and the disorder that It is being treated. Age, lean body weight, total weight, the surface area of the body, the patient's clinical condition recipient and the experience and assessment of the clinician or doctor practical that administers the therapy are among the factors that influence the selected dose. Other factors include the path of administration, the patient, the patient's medical history, the severity of the disease process, and the potency of the compound in particular. The dose should be sufficient to improve the symptoms or signs of the disease treated without producing a toxicity unacceptable to the patient.

Broadly, the scheduled oral dose It ranges from 0.1 mg to 1000 mg once or twice a day. When using Telmisartan as a prototype agent for the purposes of this invention, the convenient oral dose for an adult patient is of approximately 80 mg up to 160 mg daily but could be less or higher depending on the prescription. The interval of Dosage for topical treatment is approximately 0.1% up to 1% (weight / volume), in a gel, cream or ointment, applied twice daily. Ususal dose for intramuscular injection or intraocular is 0.25 to 2.5 mg, depending on the compartment of the eye to be treated and body mass lean of the patient. The typical dose for administration intradermal in an adult patient would be between 50 and 250 mg daily, administered in a single dose or divided into several dose depending on the criteria of the practicing physician.

Compounds and formulations

Compounds useful for the application of Methods described in this application include all existing synthetic or natural agents that not only increase the activity of gamma PPARs, but also block or antagonize the activity of angiotensin II type 1 receptor, as well like those still to discover that they have such double ability. Preferred compounds for the purposes of this invention include telmisartan (Micardis®), Irbesartan (Avapro®), as well as any derivative or formulation of these and any new ARB that can be marketed in the future that has the ability to activate gamma PPARs.

For oral administration, they can be prepared both dosage forms of solid and liquid units. For the preparation of solid compositions such as tablets, the compound of interest is mixed with the formulations of conventional ingredients such as talc, stearate magnesium, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar materials such as pharmaceutical diluents or bearers - The capsules are prepared by mixing the compound of interest with an inert pharmaceutical diluent and filling with the mix a hard gelatin capsule of appropriate size. The Soft gelatin capsules are prepared by a machine encapsulation of a suspension of the compound of interest with a suitable vegetable oil, light fluid petrolatum or other oil inert. Dosage forms of the units of fluids for oral administration, such as syrups, elixir and suspensions. Water soluble forms can be dissolved in a aqueous vehicle together with sugar, flavoring agents aromatic and conservative to form a syrup. Can be prepared an elixir through the use of a hydroalcoholic vehicle (for example, ethanol) with suitable sweeteners such as sugar and saccharin, together with an aromatic flavoring agent. The suspensions can be prepared with an aqueous vehicle with the help of a suspending agent such as acacia, tragacanth, methylcellulose and others like that.

The appropriate formulations for use parenteral are obvious to the practical doctor with a skill ordinary. Usually, the therapeutic compound is prepared in a aqueous solution (discussed below) in a concentration from about 1 to about 100 mg / ml. More commonly, the concentration ranges from about 10 to 60 mg / ml or approximately 20 mg / ml Concentrations below 1 mg / ml may be necessary in some cases depending on the solubility and potency of the compound chosen to be used. The formulation, which is sterile, is convenient for several routes topical or parenteral, including the sublingual, by suppository (for example, rectal or vaginal application), oral, intravascular, intradermal, inhalation, intramuscular, via articular, intravenous or other parenteral route.

In addition to the therapeutic compound, the compositions may include, depending on the formulation and the desired mode of administration, pharmaceutically acceptable, non-toxic carriers or diluents, which include vehicles commonly used to form pharmaceutical compositions for Animal or human administration. The diluent is selected from so that it does not unduly affect the biological activity of the combination. Examples of such diluents which are Especially useful for injectable formulations are: water, different organic or inorganic saline solutions, solution of Ringer, detrose solution, and Hank's solution. Besides, the pharmaceutical composition or formulation may include additives such as carriers, adjuvants or pharmaceutical stabilizers, not therapeutic, non-immunogenic and other similar.

In addition, excipients may be included in the formulation. Examples include cosolvents, surfactants, oils, humectants, emollients, preservatives, stabilizers and antioxidants. Any buffer can be used pharmacologically acceptable, for example, tris buffers or phosphates Effective amounts of diluents, additives are considered and excipients at those amounts that are effective to obtain a pharmaceutically acceptable formulation in terms of solubility, biological activity, etc.

The term "unit dosage form" refers to physically separate unit dosages for humans and animals, each unit containing a quantity default active material calculated to produce the effect Desired pharmacist in association with the required diluent carrier or pharmaceutical vehicle. The specifications for unit dosage forms in this invention are dictated by and depend on: (a) the unique characteristics of the material active and the particular effect to be achieved (b) the limitations inherent in the compound mixing technique such as an active material to be used in humans and animals. Examples of unit dosage forms are: tablets, capsules, pills, papers, wafers, suppositories, granules, capsules, teaspoons, tablespoons, drippers, ampules, jars, Dosed aerosols, segregated multiple of any of the above forms and other forms as described herein request.

Hence, a composition includes a compound therapeutic that can be formulated with conventional vehicles Pharmaceutically acceptable for topical, oral or parenteral Formulations can also include small amounts of adjuvants such as buffers and agents conservation to maintain isotonicity, stability Physiological and pH. The means of preparation, formulation and Administration are known to those skilled in the art. See from General form Pharmaceutical Sciences, from Remington 15th ed, Mack Publishing Col, Easton, Pa. (1980).

To prepare a topical formulation for the treatment of ophthalmological, dermatological or other disorders named in Tables I through X, a concentration is placed therapeutically effective compound in a dermatological vehicle as known in the art. The amount of the therapeutic compound to be administered and the concentration of the compound in the Topical formulations depend on the vehicle system administration or of the selected medium, side effects and the stability of the compound in the formulation. Therefore the doctor uses the appropriate preparation containing the concentration appropriate therapeutic compound and select the amount of administered formulation, depending on clinical experience with the patient in question or with similar patients.

The therapeutic compound is administered topically optionally by using a system intradermal therapy (see Barry, Dermatological Formulations (1983), p. 181 and literature cited in this application). While such topical administration systems have been designed primarily for intradermal administration of low molecular weight drugs, by definition, these can be administered percutaneously. They can adapt quickly to the administration of the therapeutic compounds of the invention by proper selection of the microporous membrane speed controller

For ophthalmic applications the compound Therapeutic is formulated in solutions, suspensions and ointments appropriate for use in the eyes. The concentrations are usually as set forth above for preparations Topical-local. For ophthalmic formulations, see Mitra (ed.) Ophthalmic Drug Delivery Systems, Marcel Dekker, Inc., New Cork, N.Y. (1993) and also Havener, W. H., Ophthalmic Pharmacology, C. V. Mosby Co., St. Louis (1983)

The concentration of the therapeutic compound used depends on the administration mode. For ophthalmic formulations  topical and extraocular, the concentration of the therapeutic compound is between an approximate range of 0.01% weight / weight (w / w) to 10% p / p. Typically, the concentration of the therapeutic compound for this form of administration is between an approximate interval of 0.025% w / w to 2.5% w / w. Both solid dispersions can be used as solubilized preparations of the therapeutic compound. For intraocular formulations (chemical administration or administration by means of an invasive device), the compound therapeutic is administered in concentrations sufficiently high to reach a final concentration between an interval Approximately 0.1: mol / L to 10: mol / L inside the compartment ophthalmic object of treatment (eg the posterior chamber in the retinal disease treatments). Typically, for this mode of administration, the final concentration of the compound Therapeutic is between an approximate range of 0.25: mol / L to 5: mol / L. Solid dispersions of the therapeutic compound can be used as well as solubilized preparations. In this way, the concentration precise is subject to experimental, modest manipulation but not improperly and completely within the doctor's abilities common practitioner, with the purpose of optimizing the response therapy. Appropriate vehicles include oil emulsions in water and water in oil for the preparation of ointments using mineral oils, petrolatum, lanolin, glycerin and the like as well as gels like hydrogel. A preferred embodiment of the present invention involves the administration of implants semi-solids or solids containing PPAR antagonists gamma

They can be used, together with the compositions described in the present application, administration systems of prolonged or slow release, which include any of the various biopolymers (biological based systems), systems that they use liposomes, colloids, resins and other application systems polymeric or compartmentalized reservoirs with the objective of provide a source of the continuous or long therapeutic compound term. These slow-release systems are applicable to Formulations for topical, intraocular, oral application and parenteral pathways.

As mentioned above, intravascular, joint, intramuscular, intradermal or other parenteral administration can be carried out through injection, cannula or other invasive device designed to introduce precisely measured amounts of a formulation into a particular compartment or tissue. . For example, application in certain areas of the eye, in situ , can be done through injections, cannulas or other invasive devices designed to introduce precisely measured quantities, directly or contained in a reservoir for slow release in situ , of a formulation desired in a compartment or tissue within the eye (eg anterior or posterior chamber, uvea or retina). Preferably, a solid or semi-solid implant can be administered subretinally using the instrumentation and methods described in US Patent 5,817,075 and US Patent 5,868,728.

Combined use of drugs

A compound as described herein. application can be used in combination with an agent to treat the diabetes mellitus, an agent to treat complications diabetics, an antihyperlipidemic agent, a hypotensive agent or antihypertensive, an antiobesity agent, a diuretic, an agent chemotherapeutic, an immunotherapeutic agent and an agent immunosuppressive and its similar (which we will refer to in forward as concomitant agent). In this case, the periods of treatments with a compound and with a concomitant agent are not particularly limited, and such agents can be supplied to a patient simultaneously or every certain time interval. The Concomitant drug dose can be properly determined based on the usual clinical dose. The proportion, between compound according to the present invention and a concomitant agent can be determined appropriately based on several factors as the subject to be treated, the route of administration, the disease or disorder to be treated and the combination of drugs. For example, when a human is treated, the parts by weight of a compound according to the present invention they are combined with 0.01 to 100 parts per weight of a concomitant agent.

Examples of an agent to treat diabetes mellitus are an insulin formulation (eg formulations of animal insulin extracted from the pancreas of a beef or a pig; a human insulin simulation synthesized by means of technologies of genetic engineering using microorganisms or methods), an agent insulin sensitivity enhancer (eg hydrochloride pioglitazone, troglitazone, rosiglitazone and its similar), a alphaglucosidase inhibitor (eg voglibose, acarbose, miglitol, emiglitato and its similar ones) a bioguanide (eg fenformin, metformin, buformin and the like) or a sulfonylurea (ex. tolbutamide, glibenclamide, gliolazide, chlorpropamide, tolazamide, acetohexamide, glucopiramide, glimepiride and the like) as well as other agents that stimulate insulin secretion. (ex. repaglinide, senaglinide, nateglinide, GPL-1 and its similar) amirin antagonists (eg pramlintida and its similar), phosphotyrosine phosphatase inhibitor (eg acid vanadic and its similar) and its similar.

Examples of agents for treating Diabetic complications are an aldose reductase inhibitor (eg. tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidareatat, SK- 860, CT-112 and similar) a factor neurotrophic (eg NGF, NT-3, BDNF and similar) PKG inhibitor (eg LY-333531 and its similar), AGE inhibitor (eg ALT946, pimagedine, piradoxamine, bromide phenacylthiazolium (ALT766) and its similar) a suppressing agent of active oxygen (e.g. thiotic acid or derivative thereof, a bioflavonoid including flavones, isoflavones, flavanones, procyanidins, anthocyanidins, picnogenol, xanthophyll, lycopene, vitamins E, coenzymes Q and the like) a dilating agent cerebrovascular (eg thiapride, mexilethene and the like).

An antihyperlipidemic agent can be, by example, a statin-based compound, which is an inhibitor of cholesterol synthesis (eg pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin and its similar) a squalene synthetase inhibitor or a compound of fibrillation that has a triglyceride reducing effect. (ex. genfibrozil, bezafibrate, clofibrate, symphibrate, clinofibrate and their Similar.

A hypotensive agent can be, for example a angiotensin converting enzyme inhibitor (eg captopril, enalapril, delapril, benazepril, enalaprilat, fosinopril, lisinopril, moexipril, perindopril, quinapril, rammipril, trandolapril and its peers) or an angiotensin II antagonist (eg losartan, cilexcetyl candesartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan and its similar.

An antiobesity agent can, for example be a central antiobesity agent (eg dexfenfluramine, fenfluramine, Phentermine, sibutramine, amphepramon, dexafetamine, mazindole, phenylporpanolamine, clobenzorex and the like) an inhibitor of pancreatic lipase (eg orlistat and its similar) antagonist of β 3 (eg CL-316243, SR-58611-A, UL-TG-307, SB- 226552, AJ-9677, BMS-196085 and similar) an appetite suppressant agent based on peptides (eg leptin, CNTF and its similar) a cholecystokinin agonist (eg. lintitript, FPL-15849 and similar) and others by the style.

A diuretic can be, for example a derivative of xanthine (eg sodium theobromine salicylate, salicylate Theobromine calcium and the like). A thiamine formulation (eg etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, bentylhydrochlorothiazide, penflutizide, polythiazide, methiclotiazide and the like), antialdosterone formulation (eg spironolactone, triamterene and its similar), a dexcarbonoxylase inhibitor (eg acetazolamide and their similar) a formulation of chlorobenzenesulfonamide (eg. chlorthalidone, mefruside, endapamide and its similar) azosemide, isosorbide, ethacrynic acid, pyretanide, bumetanide, furosemide and its similar.

A chemotherapeutic agent can be, by example, alkylating agent (eg cyclophosphamide, ifosfamide and its similar), a metabolism antagonist (e.g., methotrexate, 5-fluorouracil and its similar), an antibiotic anticancer (eg mitomycin, adriamycin and the like) a plant derived anticancer agent (eg vincristine, vindesine, taxol and the like) cisplatin, carboplatin, etoposide and its similar. Among these substances, derivatives of fluoruracil-5 such as furtulon and neofurtulon are preferred.

An immunotherapeutic agent can be, by example, a microorganism or a bacterial component (eg derivative of muramyl dipeptide, picibanil or the like), a polysaccharide that has immune enhancing activity (eg lentinan, sizofilan, krestina and its similar), a cytokine obtained by means of genetic engineering (eg interferon, interleukin (IL) and its similar), a growth factor that stimulates colonies (eg granulocyte colony stimulating factor, erythropoetins and its similar), and similar, among these substances, those Preferred are IL-1, IL-2, IL-12 and its similar.

An immunosuppressive agent may be by example a calcineurin inhibitor / immunophilin modulator such as cyclosporine (Sandimune, Gengraf, Neoral), tacrolimus (Prograf, FK506), ASM 981, sirolimus (RAPA, rapamycin, Rapamune), or its derivative SDZ-RAD *, a glucocorticoid (prednisone, prednisolone, methylprednisolone, dexamethasone and its similar), an inhibitor of purine synthesis (mycophenolate mofetil, MMF, CellCept (R), azathioprine, cyclophosphamide) a interleukin antagonist (basiliximab, daclizumab, deoxispergualine), a lymphocyte emptying agent such as antimocyte globulin (thymoglobulin, lymphoglobulin), antibody antiCD3 (OKT3 *) and their peers.

In addition, an agent whose effect of improvement on cachexia has been established in an animal or clinical phase model, such as a cycloxygenase inhibitor (eg indomethacin and its similar) [Cancer Research, Vol. 49, page 5935-5939, 1989 ] (Cancer Research Vol. 49, p. 5935-5939, 1989), a progesterone derivative (eg megesterol acetate) Journal of Clinical Oncology, Vol. 12, page 213-225, 1994] (Revista de Clinical Oncology, Vol. 12, p. 213-225, 1994), a glucosteroid (eg dexamethasone and the like), a methoclopramide-based agent, a tetrahydrocannabinol-based agent ( supra ), a metabolism-enhancing agent lipids (eg eicosapentanoic acid and its similar) [British Journal of Cancer, Vol. 68, page 314-318, 1993] (British Cancer Magazine, Vol. 68, p. 314-318, 1993), a growth hormone , IGF-1, or an antibody against TNF-alpha, LIF, IL-6, oncostatin M which are factors that induce cachexia can also to be used concomitantly with a compound according to the present invention.

Possible preferred combinations of Diabetes prevention agents are, an activator of PPARgamma with ARB activity, and:

one.

a formulation of insulin and a biguanide;

2.

a sulfanylurea agent and a biguanide

3.

a sulfanylurea agent and an inhibitor of alpha glucosidase

Four.

a biguanide and an inhibitor of alpha glucosidase

5.

a blood sugar reducing agent and the other types of agents to treat diabetic complications.

6.

A reductase inhibitor 3.hydroxy-3-methylglutaryl coenzyme A (HMG CoA)

7.

Any other of the two types of agents mentioned above

8.

A agent that inhibits the activity of the converting coenzyme of angiotensin

In case the compound or composition is use in combination with the other agent, an amount of each of they can be reduced between an interval that is safe in view to its adverse effects. Especially, an agent that increases the Insulin sensitivity, a biguanide or a sullfonylurea agent they can be used in doses lower than the regular dose so that adverse effects that can cause these agents are avoided safe way. In addition, an agent to treat complications diabetics, an antiperipidemic agent and a hypotensive agent they can also be used in smaller doses so that the effect adverse that may be caused by them be avoided in a way safe.

As noted above, when administering both an ARB and a PPAR activator formulated together in a single tablet or tablet, you can treat glucose intolerance or type 2 diabetes and other disorders sensitive to PPARs without cause fluid retention, edema or heart failure congestive With this purpose, you can prepare and use a pharmaceutical composition consisting of (i) a PPAR activator in a therapeutically effective amount sufficient to Prophylactically prevent, slow down, delay or treat disorders  metabolic, inflammatory, atopic, autoimmune, proliferative, or cardiovascular in humans; (ii) a receptor antagonist of angiotensin II type1 in a therapeutically effective amount enough to prevent, slow down, delay or treat retention of fluids, peripheral edema, pulmonary edema or insufficiency congestive heart; and (iii) a pharmaceutically carrier acceptable. For this purpose, the PPAR activator in the pharmaceutical composition can be a thiazolinidinedione selected from a group of compounds consisting of rosiglitazone, KRP 297, MCC-555, R-483, CS-011, NC2100, DRF-2189, PAT-5A, NIP-221, netoglitazone, rivoglitazone and balagitazone, or an analogue thereof, or a tautomeric form of the same, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof. Alternatively, the PPAR activator in the composition pharmaceutical can be a non-thiazolidinedione selected from the group of compounds consisting of tesaglitazar, farglitazar, ragaglitazar, LY818, T131, LSN862, DRF 4832, LM 4156, LY 510929, LY 519818, TY 51501, X 334, or an analogue thereof, a form tautomeric thereof, a pharmaceutically acceptable salt of the same, or a pharmaceutically acceptable solvate thereof. Other thiazolidinedione PPAR activators can also be used. or not thiazolidinedione that are known to experts in the technique. With the purpose of making the pharmaceutical composition, the angiotensin II type1 receptor antagonist may be a compound selected from the group consisting of telmisartan, Irbesartan, Valsartan, Osartan, Candesartan Cilexetil, Olmesartan, olmesartan medoximil, losartan, valsartan, eprosartan, irbesartan, tasosartan, pomisartan, ripisartan and fozartan, or an analogue of same, a tautomeric form thereof, a salt pharmaceutically acceptable thereof, or a solvate pharmaceutically acceptable thereof.

The compounds can also be administered orally in combination with natural or synthetic compounds that the activity of the retinoid X receptor is combined or modified to provide a synergistic effect in the treatment or prevention of the disorders mentioned in the tables from I to X. The examples of such compounds that provide a synergistic effect when administered in combination with the drugs included in the present invention include vitamin D analogs, various retinoic acid derivatives and other ligands for receptors of retinoid X or retinoic acid receptors including but not limited to compounds such as LG100268, tazarotene, TTNPB, AGN 190121, adapalene or LGD1069 (Targretin).

Therapeutic effects can be achieved synergistic by oral or topical administration of drugs included in the present invention together with administration by oral, topical or intravenous route of drugs that bind and modify the activity of either vitamin D receptors, the glucocorticoid receptors, the intracellular enzyme calcineurin, retinoid X receptors, retinoic acid receptors or other PPARs such as PPARalfa or PPARdelta. A dose range of preferential administration of a retinoic acid derivative or retinoid would typically be 0.1 to 100 mg per square meter of body surface area, depending on the ability of the drug to combine or modify the activity of its receptor cognate nuclear, supplied in single or fractional doses orally or by continuous infusion, two or three times a day. For synergistic treatment, doses, routes and frequency of administration preferred in the administration of the analogs of Vitamin D or retinoid compounds may be similar to dose, routes and frequency of administration of these agents when They are administered without PPAR activators. Examples of retinoids effective are 9-cis retinoic acid, 13-cis retinoic acid, all acids transretinoic (at-RA). Preferred retinoids for this purpose would include 13-cis retinoic acid, Tazarotene or Targretin. A preferred dosage range for systemic administration of a vitamin D analog would typically range from 0.1 to 100 mg per square meter of the area of total body surface, depending on the ability of the drug to combine / bind and / or activate its receptor cognate vitamin D, given as a single or fractional dose, oral or by continuous infusion, two or three times a day. Examples of Effective vitamin D analogues are 1,25-dihydroxy vitamin D, calcipotriene and Calcipotriol The dose interval and routes and frequency of administration of the PPAR activators required to obtain synergistic effects when administered with vitamin D or derivatives of retinoid are the same as those described elsewhere of the present application. The preferred mode of administration of these drugs with synergistic therapeutic purposes would be the oral although alternatively administration routes can be used Topical or parenteral. Doses and modes and frequency of administration of vitamin D or compounds related to Retinoid in synergistic topical therapies will be similar to those which are ordinarily recommended for these agents when Manage without activators of PPARs. The dose interval and the modes and frequency required for topical administration of the thiazolidine flavonoid derivatives administered in combination with vitamin D or retinoid related compounds are the same as those described elsewhere in this request.

Therapeutic effects can be achieved synergistic by oral or topical administration of drugs comprised in the present invention together with antioxidants synthetic or natural administered orally, topically or intravenously. These include ascorbic acid and its derivatives (eg Vitamin C) tocopherols (eg Vitamin E, vitamin E succinate), carotenes and carotenoids (eg. β-carotene), acid alpha-lipoic, probucoles, flavones, isoflavones and flavonols (eg quercetin, genistein, catechin, apigenin, lutein, luteolin) lycopene, picnogenol, glutathione and its derivatives (eg acetylocysteine and dithiothreitol) and phytoestrogens and phenolic anthocyanidin and procyanidin derivatives (eg. resveratrol, cyanidine, cinnamic acid)

The compounds described herein request are also useful to suppress mediators of the neurogenic inflammation (example substance P or tachykinins) and they can be used in the treatment of rheumatoid arthritis; psoriasis; topical inflammations such as those associated with burns solar, eczema or other sources of pruritus and allergies, including asthma. The compounds can also function as neuromodulators of the central nervous system, with applications useful in the treatment of Alzaheimer's disease and others forms of dementia, pain (as a spinal analgesic), and pains of head. In addition, in disorders that include myocardial fibrosis, myocardial ischemia, pathological conditions secondary to autoimmune response to homograft transplants, splenic bleeding, including liver fibrosis, cirrhosis and esophageal varicose veins, the compounds of the invention can provide cytoprotection.

The present invention is further detailed. extensively in the following Examples and Methods which do not They are intended to restrict the present invention.

Method to design and identify an ARB as a PPAR ligand

ARBs, or derivatives thereof, can analyze to know your ability to activate the various PPAR isoforms using standard screening methods known to those skilled in the art including, but not limited to cell-based transactivation assays or cell-free assays that test the ability of a compound to activate the structure of a PPAR by measuring the output of a signal reporter that reflects the extent of PPAR activation. By example, the telmisartan angiotensin receptor blocker is add to the culture medium CV1 cells or other cells that can be translated with a full or partial length sequence of PPAR DNA next to a reporter structure that contains a PPAR response element or other response element appropriate fused to a reporter gene like luciferase. The Telmisartan's ability to activate gamma PPARs is tested measuring the activity of the luciferase reporter gene and it is observed that Telmisartan causes a significant increase in the activity of reporter gene well above the original level present in the cells that were not treated with telmisartan. Experiments similar are made with irbesartan which is also known to Activate gamma PPARs. Any ARB that is known to activate PPARs gamma according to these or other methods can be used to treat known disorders are sensitive to activators of PPARs

Modifications can also be made. chemical to existing ARBs that are known in advance that can increase your ability to activate gamma PPARs. Therefore, it can design ARBs that are particularly effective in dealing with known disorders are sensitive to PPAR activators without causing fluid retention, edema or heart failure. Chemical structures of activators can also be modified of PPARs to increase their ability to inhibit the activity of RCT or block angiotensin receptors. This can be achieved using published information about the crystalline structures of PPARs and published information on waste from amino acids and regions of the PPARs that are important in the receptor activation alongside known methods to test the ability of the compounds to inhibit the activity of RCTs or block angiotensin receptors. Using methods known to those skilled in the art, can be performed chemical modifications to existing ARBs or inhibitors of ECA or design derivatives thereof that is known in advance that have increased the ability to activate PPARs more effectively than ARBs and existing ACE inhibitors.

Method to identify a PPAR ligand with lower risk of cause fluid retention, edema or heart failure congestive

Gamma PPAR activators that have improved their safety profile and decreased the risk of causing fluid retention, edema or congestive heart failure can be identified by testing their ability to inhibit the activity of the angiotensin converting enzyme or their ability to block the receptor of angiotensin. PPARs gamma ligands or activators of gamma PPARs that also inhibit ACE activity or block angiotensin II type 1 receptors represent an improvement over existing PPAR ligands to treat disorders sensitive to PPARs because they have reduced the chances of cause fluid retention, edema or congestive heart failure. A variety of assays are available and can be used by those skilled in the art to determine if a gamma PPAR activator can also block angiotensin II type 1 receptors or inhibit the activity of the angiotensin converting enzyme. According to the method of Groff JL, et al . (Simplified enzymatic study of serum angiotensin converting enzyme. Clin Chem. 1993; 39: 400-4) or other studies with which those skilled in the art are familiar with analyzing components in order to know their abilities to inhibit angiotensin converting enzyme activity.

The activity of a PPAR ligand to block selectively the interaction of angiotensin II (AII) with the angiotensin II type 1 receptor can be determined by the competitive binding method of angiotensin II labeled radioactively with preparations enriched in type AII receptor 1 vs. AII type 2 receptor. Other methods with which they are familiar art experts to identify compounds that block angiotensin II type 1 receptor they can also be used to determine if a PPAR activator can block the angiotensin II type 1 receptor in any degree that would be useful to identify a PPAR activator that is unlikely to cause fluid retention, edema or insufficiency congestive heart

Examples

The following examples are provided for provide knowledgeable technical experts common a complete exposition and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors estimate how their invention is not intended to represent that the following experiments are all nor the only ones experiments carried out. Efforts have been made to ensure accuracy with respect to the numbers used (example: quantities, temperature, etc.) but some errors and deviations They must be taken into account. Unless stated otherwise, the parts are parts by weight, the molecular weight is the average weight of molecular weight, the temperature is in degrees Celsius, and the pressure is atmospheric or almost atmospheric.

Example 1 Identification of angiotensin receptor blockers II type1 that activate gamma PPARs

The activity of PPARγ was determined at through CV-1 cell assays (CCL-70 ATCC line; Bethesda, Maryland) transduced using the GenePorter transduction reagent (Systems of Gene Therapy, San Diego, California) to carry 200 ng of PPARγ expression plasmids and 1 µg plasmids Luciferase reporters and 400 ng of pCMVSport β-al (Gibco, Grand Island, New Jersey) as internal control. 24 hours after transfection, the cells were treated with various concentrations of compounds test (telmisartan, irbesartan, valsartan, losartan, metabolites losartan assets, active forms of candesartan and olmesartan, rosiglitazone, or pioglitazone) and incubated for 24 hours additional. Cell fragments were analyzed to find Luciferase and β-galactosidase activity using Promega test systems (Madison, Wisconsin). All the treatments were performed three times and were normalized for β-galactosidase activity. Concentrations antagonistic who reported half of the maximum activation (EC50 values) were calculated using the GraphPad Prism version 3.03 (GraphPad Software, nc., San Diego, California).

Telmisartan significantly activated the PPARγ (5-8 parts) when tested in concentrations (1-5 PM *) that can be reached with conventional oral dosages [Stangier, 2000 # 14424]. He Telmisartan worked as a PPAR? antagonist moderately powerful (EC50 = 5.6 PM), activating the receiver between 25% -30% of the maximum level of activity achieved by Total antagonists pioglitazone and rosiglitazone. Irbesartan activated the PPARγ (activation 2-3 times) when It was tested at 10 µM. None of the other ARBs tested caused no significant activation of PPARs even when tested at higher concentrations (more than 10 µM). These experiments show that two receptor blockers of known angiotensin, telmisartan and irbesartan, are also activators of gamma PPARs. As the activators of PPARs Gamma can be used to prevent type 2 diabetes, the syndrome metabolic and other clinical disorders sensitive to treatment with PPAR activators, these experiments demonstrate the usefulness of telmisartan and irbesartan for the prevention and treatment of type 2 diabetes, metabolic syndrome and other disorders known for their sensitivity to treatment with activators of PPARs

Example 2 Measurement of adipocyte differentiation activity in vitro

The following examples 2 and 3 provide a generic means of measuring adipocyte differentiation for determine if anyone has an insulin sensitizing agent. A mouse preadipocyte cell line (3T3-L1) obtained from the American type culture collection, and the cells are grown in a modified Dulbecco Águila medium (Dulbecco's modified Eagle medium) (DMEM *) containing 4.5 g / L glucose, 50 mg / L streptomycin sulfate, 100,000 units / L of Penicillin-G, 0.584 g / L of glutamine-L, 4 mg / L pantothenate, 8 mg / L biotin-D, and 10 mM HEPES (pH 7.2)] supplemented with 10% fetal bovine plasma (PFB). The cells then placed in 1.5 x 104 / cm2 plates on a culture plate 96 appropriate tissue (observation plate, white 96, Pachard) type 1 collagen coated. After the cells reached confluence, the cells were also grown in a medium of DMEM differentiation supplemented with 5% PFB, 100 ng / mL of insulin, 0.1 nM of isobutylmethylxanthine (IBMX) and 1 nM of dexamethasone and containing various concentrations of the compounds for 4 days The compounds added from a solution of reproduction of dimethylsulfoxide (DMSO). The final concentration of DMSO in the differentiation medium does not exceed 0.1% (v / v). The DMSO (0.1%) was added to the control cultures. The medium was replaced with a maintenance medium (DMEM supplemented with 5% PFB and 100 mg / mL insulin), and the cells were cultured for 2 more days. The activity of stimulation of adipogenesis was determined by exposing the cells to acid acetic [14-C] (7.4 kBq / mL) and an absorption of acetic acid [14-C] monitored 1 hour after incubation The medium is discarded and the cells are washed two times with a phosphate buffered saline solution. The cells air dried and 200 mL of sparkling cocktail are added (Microscint-20, Packard) to the cells, and it they have a Packard Topcount microplate scintillation counter. Stimulation of adipogenesis is expressed as concentrations. equivalent to the marked absorption values [14-C] in treatment with 10 uM of Telmisartan

Example 3 Measurement of insulin-sensitizing activity in vivo

The hypoglycemic activity of the compounds of test in insulin-resistant rats obese fat (fa / fa *) of Zucker type. (Jackson Laboratory, Bar Harbor, ME). These rats are greatly insulin-resistant with extremely high blood insulin levels. Are used Lean litter mates as controls. Each compound of test is administered to three Zucker rats at a rate of 10 mg / kg daily for five days after which samples are taken from blood in a state of no fasting. Blood samples are collected, collected. placed in a centrifuge with hematocrit tubes and are centrifuged to obtain plasma. Insulin in plasma collected is measured through a radioimmunoassay equipment (Linco Research, Inc, St Charles, MO). Activity insulin-sensitizing test compounds It is calculated as described below:

Activity sensitizing insulin (%) = [(PI in C - PI in T) / PI in C] x 100

Where "PI in C" is plasma insulin in the control rats and "PI in T" is plasma insulin in the rats treated with test compounds.

Example 4 Clinical trial where a gamma PPAR activator is used to treat type 2 diabetes without causing fluid retention, edema or heart failure

A woman of 49 years with hypertension, hypertriglyceridemia and type 2 diabetes. Before starting to administer telmisartan, the patient had a blood pressure of 160/90 mmHg, fasting serum glucose of 183 mg / dl, fasting serum triglyceride level of 264 mg / dl and an HDL cholesterol level of 48 mg / dl. The patient is taking another type 2 diabetes drug but the dose of this drug It remains constant during this study. It is administered to the Telmisartan patient (Micardis®) in an oral dose of 80 mg per day. After 3 weeks of treatment with telmisartan, the pressure arterial reduction to 143/91 mm / Hg with little or no improvement in fasting glucose (1888 mg / dl), triglycerides (281 mg / dl) or levels of HDL cholesterol (50 mg / dl). So, the oral dose of telmisartan (Micardis®) is increased to 160 mg daily. After 7 weeks of treatment with 160 mg daily of telmisartan (Micardis®), the The patient's blood pressure is reduced to 131/81 mmHg and there is a Diabetes improvement with glucose level reduced to 145 mg / dl, the triglyceride level is reduced to 178 mg / dl and the HDL cholesterol increased to 60 mg / dl. The clinical examination does not reveal no evidence of increased fluid retention, edema peripheral, pulmonary edema or congestive heart failure. Be continue treatment with telmisartan (Micardis®) according to the criteria of the clinician with the objective of maintaining improvement in the control of the patient's blood pressure and diabetes of type 2.

Example 5 Clinical trial in which a gamma PPAR activator is used to treat metabolic syndrome without causing fluid retention, edema or heart failure

A woman of 59 is selected for treatment years with the metabolic syndrome. Before starting to administer the telmisartan, the patient had a blood pressure of 160/79 mmHg, fasting serum glucose of 118 mg / dl, insulin level in fasting 15 micro units / ml, fasting triglycerides of 129 mg / dl and a waist circumference of 120 cm. The patient has the metabolic syndrome according to the definition provided by the Program National for Cholesterol Education. Syndrome metabolic is associated with an increased risk to develop type 2 diabetes 5-9 times and an increased risk of cardiac mortality 2-3 times. To the patient You are given telmisartan (Micardis®) in an oral dose of 80 mg daily to treat metabolic syndrome. After 2 weeks of Telmisartan treatment, the patient no longer meets the criteria for the diagnosis of metabolic syndrome and its pressure arterial is reduced to 130/69 mmHg, fasting glucose is normalized at 105 mg / dl and the fasting triglyceride level is reduced to 115 mg / dl The clinical examination reveals no evidence of any increase in fluid retention, peripheral edema, pulmonary edema or congestive heart failure Telmisartan treatment (Micardis®) is continued according to the clinician's criteria with the objective of preventing the recurrence of metabolic syndrome and prevent the development of type 2 diabetes.

Example 6 Clinical trial in which PPARgamma activators are used to treat inflammation without causing fluid retention, edema or heart failure

A woman of 57 is selected for treatment years with osteoarthritis and inflammation diagnosed from elevated levels of C-reactive protein (PRC) before administer telmisartan, the patient had a notable increase in serum PRC level of 7.9 mg / L indicator of active inflammation. TO the patient is given telmisartan (Micardis®) in one dose 80 mg oral daily. After 6 weeks of treatment with Telmisartan, the PRC level is reduced to 4.1 mg / L. After 9 weeks of treatment the level of PRC remains reduced to 3.9 mg / L and the Symptoms of inflammation and osteoarthritis are stabilized. The exam clinical does not reveal evidence of increased fluid retention, peripheral edema, pulmonary edema or heart failure congestive Treatment with telmisartan (Micardis®) is continued according to the criteria of the clinical doctor with the objective of maintaining the improvement in inflammation control.

References Examples of ARBs included in this invention

1. Maillard MP, Wurzner G, Nussberger J, Rye C, Burnier M, Brunner HR. Comparative angiotensin II receptor blockade in healthy volunteers: the importance of dosing. Clin Pharmacol Ther. 2002 ; 71: 68-76.

2. Almansa C, et al . Synthesis and structure-activity relationship of a new series of potent AT1 selective angiotensin II receptor antagonists: 5- (biphenyl-4-ylmethyl) pyrazoles. J Med Chem. 1997 ; 40: 547-58.

3. Almansa C, et al . Diphenylpropionic acids as new AT1 selective angiotensin II antagonists. J Med Chem. 1996 ; 39: 2197-206.

4. Le Bourdonnec B, et al . Synthesis and pharmacological evaluation of new pyrazolidine-3, 5-dions as AT1 receptor antagonists. J Med Chem. 2000 ; 43: 2685-97.

5. Almansa C, et al . Diphenylpropionic acids as new AT 1 selective angiotensin II antagonists. J Med Chem. 1996 ; 39: 2197-206.

6. Norman NH, et al . 4- (Heteroarylthio) -2-biphenylyltetrazoles as nonpeptide angiotensin II antagonists. J Med Chem. 1995 ; 38: 4670-8.

7. Mederski WW, et al . Non-peptide angiotensin II receptor antagonists: synthesis and biological activity of a series of novel 4,5-dihydro-4-oxo-3H-imidazo [4,5-c] pyridine derivatives. J Med Chem. 1994 ; 37: 1632-45.

8. Dhanoa DS, et al . (Dipropylphenoxy) phenylacetic acids: a new generation of nonpeptide angiotensin II receptor antagonists. J Med Chem. 1993 ; 36: 3738-42.

9. Bernhart CA, et al . A new series of imidazolones: highly specific and potent nonpeptide AT1 angiotensin II receptor antagonists. J Med Chem. 1993 ; 36: 33.71-80.

10. Atwal KS, et al . Dihydropyrimidine angiotensin II receptor antagonists. J Med Chem. 1992 ; 35: 4751-63.

11. Lin HS, et al . Nonpeptide angiotensin II receptor antagonists: synthetic and computational chemistry of N - [[4- [2- (2H-tetrazol-5-yl) -1-cycloalken-1-yl] phenylJmethyl] imidazole derivatives and their in vitro activity. J Med Chem. 1992 ; 35: 2658-67.

12. Blankley CJ, et al . Synthesis and structure-activity relationships of a novel series of non-peptide angiotensin II receptor binding inhibitors specific for the AT2 subtype. J Med Chem. 1991 ; 34: 3248-60.

13. Buhlmayer P, et al . Nonpeptidic angiotensin II antagonists: synthesis and in vitro activity of a series of novel naphthalene and tetrahydronaphthalene derivatives. J Med Chem. 1991 ; 34: 3105-14.

14. Schmidt B, Schieffer B. Angiotensin II AT1 Antagonists Receptor. Clinical Implications of Active Metabolites. J Med Chem. 2003 ; 46: 2261-70.

15. Le Bourdonnec B, et al . Comparison of 3D structures and AT (1) binding properties of pyrazolidine-3,5-diones and tetrahydropyridazine-3,6-diones with parent antihypertensive drug irbesartan. J Med Chem. 2002 ; 45: 4794-8.

16. Ellingboe JW, et al . Metabolites of the angiotensin II antagonist tasosartan: the importance of a second acidic group. J Med Chem. 1998 ; 41: 4251-60.

17. Ashton WH, et al . Triazolinone biphenylsulfonamide derivatives as orally active angiotensin II antagonists with potent AT1 receptor affinity and enhanced AT2 affinity. J Med Chem. 1994 ; 37: 2808-24.

18. Kubo K, et al . Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of benzimidazoles. J Med Chem. 1993 ; 36: 1772-84.

19. From B , et al . Discovery of a novel class of orally active, non-peptide angiotensin II antagonists. J Med Chem. 1992 ; 35: 3714-7.

20. Carini DJ, et al . Nonpeptide angiotensin II receptor antagonists: the discovery of a series of N- (biphenylylme-
thyl) imidazoles as potent, orally active antihypertensives. J Med Chem. 1991 ; 34: 2525-47.

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Examples of insulin sensitizing agents with performances that can be used to derivatize ARBs

21. Brooks DA, Etgen GJ, Rito CJ, et al . Design and synthesis of 2-methyl-2- [4- (2- [5-methyl-2-aryloxazol-4-yl] ethoxy) phenoxy] propionic acids: a new class of dual PPARalpha / gamma agonists. J Med Chem. 2001 ; 44: 2061-4.

22. Henke BR, Blanchard SG, Brackeen MF, et al . N- (2-Benzoylphenyl) -L-tyrosine PPARγ agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents. J Med Chem. 1998 ; 41: 5020-36.

23. Cronet P, Petersen JF, Folmer R, et al . Structure of the PPARa and-gamma ligand binding domain in complex with AZ 242; ligand selectivity and agonist activation in the PPAR family. Structure (Camb). 2001 ; 9: 699-706.

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Anti-inflammatory effects of ARBs

24. Wang N, et al . Constitutive activation of peroxisome proliferator-activated receptor-gamma suppresses pro-inflammatory adhesion molecules in human vascular endothelial cells. J Biol Chem. 2002 ; 277: 34176-81.

25. Brasier AR, et al . Angiotensin II induces gene transcription through cell-type-dependent effects on the nuclear factor-kappaB (NF-kappaB) transcription factor. Mol Cell Biochem. 2000 ; 212: 155-69.

26. Miyajima A, et al . Angiotensin II type 1 antagonist prevents pulmonary metastasis of murine renal cancer by inhibiting tumor angiogenesis. Cancer Res. 2002 ; 62: 4176-9.

27. Phillips MI, Kagiyama S. Angiotensin II as a pro-inflammatory mediator. Curr Opin Investig Drugs. 2002 ; 3: 569-77.

28. Miyazaki M, et al . Angiotensin II type 1 receptor antagonist, TCV-116, prevents neointima formation in injured arteries in the dog. Jpn J Pharmacol. 1999 ; 79: 455-60.

29. Sasaki K, et al . Evidence for the importance of angiotensin II type 1 receptor in ischemia-induced angiogenesis. J Clin Invest. 2002 ; 109: 603-11.

30. Silvestre JS, et al . Antiangiogenic effect of angiotensin II type 2 receptor in ischemia-induced angiogenesis in mice hindlimb. Circ Res. 2002 ; 90: 1072-9.

31. Tamarat R, et al . Angiotensin II angiogenic effect in vivo involves vascular endothelial growth factor- and inflammation-related pathways. Lab Invest. 2002 ; 82: 747-56.

32. Horiuchi M, et al . Fluvastatin enhances the inhibitory effects of a selective angiotensin II type 1 receptor blocker, valsartan, on vascular neointimal formation. Circulation 2003 ; 107: 106-12.

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The methods claimed in this invention, in part, apply to synthetic PPAR ligands or activators or Details described in detail in the following applications for published, authorized, pending or provisional patents:

33. US Pat. No. 09 / 520,208 1,2-Dithiolane Derivatives, pending

34. US Pat. No. 09 / 684,738 Novel Dithiolane Derivatives

35. US Pat. No. 6,103,742 Pharmaceutical composition

36. US Pat. No. 6,100,403 Production of benzaldehyde compounds

37. US Pat. No. 6,087,385 Flavonoid derivatives

38. US Pat. No. 6,087,384 Apoptosis inhibitor

39. US Pat. No. 6,028,088 Flavonoid derivatives

40. US Pat. No. RE36,575 Pyridine and thiazolidinedione derivatives

41. US Pat. No. 6,022,897 Selective modulators of PPAR (and methods ...

42. US Pat. No. 6,011,036 Heterocyclic compounds having antidiabetic ...

43. US Pat. No. 6,011,031 Azolidinediones useful for the treatment of diabetes ...

44. US Pat. No. 6,008,237 Arylthiazolidinedione derivatives

45. US Pat. No. 5,990,139 Thiazolidinedione derivatives or salts thereof and ...

46. US Pat. No. 5,985,884 Heterocyclic compounds, process for their preparation ...

47. US Pat. No. 5,977,365 Heterocyclic compound having anti-diabetic activity

48. US Pat. No. 5,972,970 Oxazolidinedione derivatives, their production and use

49. US Pat. No. 5,972,959 Oxime derivatives, their preparation and therapeutic use

50. US Pat. No. 5,965,589 Thiazolidinedione derivatives, their production and use

51. US Pat. No. 5,962,470 Heterocyclic compounds having anti-diabetic activity ...

52. US Pat. No. 5,952,509 Production of benzaldehyde compounds

53. US Pat. No. 5,965,584 Pharmaceutical composition

54. US Pat. No. 5,952,356 Pharmaceutical composition

55. US Pat. No. 5,939,442 Modulations of PPAR (, and methods for the use thereof

56. US Pat. No. 5,932,601 Oxazolidinedione derivatives, their production and use

57. US Pat. No. 5,925,656 Compounds having antidiabetic, hypolipidemic ...

58. US Pat. No. 5,919,782 Heterocyclic compounds having antidiabetic ...

59. US Pat. No. 5,910,592 Substituted thiazolidinedione derivatives

60. US Pat. No. 5,902,726 Activators of the nuclear orphan PPAR receptor (

61. US Pat. No. 5,889,032 Heterocyclic compounds having antidiabetic ...

62. US Pat. No. 5,889,025 Antidiabetic compounds having hypolipidaemic ...

63. US Pat. No. 5,886,014 Benzimidazole derivatives, their preparation ...

64. US Pat. No. 5,885,997 Heterocyclic compounds, process for their preparation ...

65. US Pat. No. 5,869,495 Heterocyclic compounds as pharmaceutical

66. US Pat. No. 5,859,051 Antidiabetic agents

67. US Pat. No. 5,847,008 Method of treating diabetes and related disease states

68. US Pat. No. 5,843,970 Thiazolidine derivatives for the treatment of hypertension

69. US Pat. No. 5,834,501 Heterocyclic compounds having anti-diabetic activity ...

70. US Pat. No. 5,827,865 Heterocyclic compounds as pharmaceutical

71. US Pat. No. 5,824,694 Thiazolidine derivatives for the treatment of psoriasis

72. US Pat. No. 5,811,439 Thiazolidinedione derivatives, method for preparing ...

73. US Pat. No. 5,801,173 Heterocyclic compounds having antidiabetic ...

74. US Pat. No. 5,741,803 Substituted thiazolidinedionle derivatives

75. US Pat. No. 5,693,651 Quinoline derivatives

76. US Pat. No. 5,506,245 Thiazolidinedione compounds

77. US Pat. No. 6,150,371 Method for preventing and for treating autoimmune ...

78. WO 01/12612 Benzoic acid derivatives for the treatment of diabetes ...

79. WO 98/57941 New thiazolidinedione, oxazolidinedione ...

80. WO 01/00603 Thiazole and oxazole derivatives ...

81. WO 97/25042 Use of an antagonist of PPAR-alpha and PPAR-gamma ...

82. WO 98/05331 Prevention or treatment of type 2 diabetes or cardiovascular ...

83. WO 97/28137 Heterocyclic derivatives as antidiabetic and antiobesity ...

84. WO 00/27832 PPAR γ ligands

85. WO 01/21602 Oxa- and thiazole derivatives ...

86. WO 01/34094 Novel compounds to treat diabetes...

87. WO 99/62870 New 3-aryl-2-hydroxypropionic acid ...

88. WO 99/62871 New 3-aryl-2-hydroxypropionic acid ...

89. WO 99/62872 New 3-aryl-2-hydroxypropionic acid ...

90. US Pat. No. 5,864,043 Benzimidazoles, medicaments ...

91. US Pat. No. 5,684,029 Benzimidazoles, pharmaceutical compositions ...

92. US Pat. No. 5,614,519 (1- (2.3 or4-N-morpholinoalkyl) -imidazol-4-yl) -benizimidazol-1-yl-methyl] -biphenyls useful as angiotensin-II antagonists

93. US Pat. No. 5,602,127 (Alkanesultam-1-yl) -benzimidazol-1-yl) -1yl) -methyl-biphenyls useful as angiotensin-II antagonists

94. US Pat. No. 5,594,003 Tetrahydroimidazo [1,2-a] pyridin-2-yl- (benzimidazol-1-yl) -methyl-biph enyls useful as angiotensin-II antagonists

95. US Pat. No. 5,591,762 Benzimidazoles useful as angiotensin-11 antagonists

96. US Pat. No. 5,587,393 Benzimidazoles, pharmaceutical compositions ...

97. US Pat. No. 5,565,469 Benzimidazoles and pharmaceutical compositions

98. US Pat. No. 5,541,229 Benzimidazoles and medicaments

99. US Pat. No. 6,355,808 Benzimidazole compounds, their production and use

100. US Pat. No. 6,232,334 Benzimidazole derivatives, their production and use

101. US Pat. No. 6,004,989 Benzimidazole derivatives, their production and use

102. US Pat. No. 5,962,491 Benzimidazole derivatives and use thereof

103. US Pat. No. 5,883,111 Heterocyclic compounds and their use as angiotensin ...

104. US Pat. No. 5,736,555 Heterocyclic compounds and their use as angiotensin ...

105. US Pat. No. 5,705,517 Benzimidazole derivatives and use thereof

106. US Pat. No. 5,703,110 Benzimidazole derivatives, their production and use

107. US Pat. No. 5,583,141 Heterocyclic compounds and their use as angiotensin ...

108. US Pat. No. 5,500,427 Cyclic compounds and their use

109. US Pat. No. 5,496,835 Heterocyclic compounds having angiotensin II ...

110. US Pat. No. 6,160,000 Antidiabetic agents based on aryl and heteroarylacetic acids

111. US Pat. No. 6,113,907 Pharmaceutical grade St. John's Wort

112. US Pat. No. 6,090,839 Antidiabetic agents

113. US Pat. No. 6,090,836 Benzisoxazole-derived antidiabetic compounds

114. US Pat. No. 6,020,382 Method of treating diabetes and relatad disease states

115. US Pat. No. 5,958,942 Tricyclic nitrogen ring compounds, their production and use

116. US Pat. No. 5,859,051 Antidiabetic agents

117. US Pat. No. 5,847,008 Method of treating diabetes and relatad disease states

118. US Pat. No. 5,843,172 Porous medicated stent

119. US Pat. No. 5,663,187 Treatment of atherosclerosis with angiotensin II receptor biocking imidazoles

120. US Pat. No. 5,663,186 Treatment of atherosclerosis with angiotensin II receptor biocking imidazoles

121. US Pat. No. 6,160,000 Antidiabetic agents based on aryl and heteroarylacetic acids \

122. US Pat. No. 6,479,524 Substituted aryl and heteroaryl derivatives ...

123. US Pat. No. 6,476,023 Aromatic heterocyclic compounds as anti-inflammatory agents

124. US Pat. No. 6,469,039 Disubstituted bicyclic heterocycles ...

125. US Pat. No. 6,451,832 Benzimidazoles with antithrombotic activity

126. US Pat. No. 6,414,008 Disubstituted bicyclic heterocycles ...

127. US Pat. No. 6,372,773 Aromatic heterocyclic compounds as antiinflammatory agents

128. US Pat. No. 6,358,945 Compounds useful as anti-inflammatory agents

129. US Pat. No. 6,333,325 Method of treating cytokine mediated diseases or conditions

130. US Pat. No. 6,329,415 Aromatic heterocyclic compounds as antiinflammatory agents

131. US Pat. No. 6,150,371 Method for preventing and for treating autoimmune disease

132. US Pat. No. 6,117,893 Heterocyclic compounds having anti-diabetic activity ...

133. US Pat. No. 6,414,002 Substituted acid derivatives useful as antidiabetic and antiobesity agents ...

134. US Pat. No. 6,432,996 Pharmaceutical composition

135. US Pat. No. US Pat. No. 6,432,993 Substituted fused heterocyclic compound (rivoglitazone) ...

136. US Pat. No. US Pat. No. 6,486,188 Method of treatment for cardiovascular complications

137. US Pat. No. 6,420,405 Pharmaceutical composition for angiotensin ll-mediated ...

138. US Pat. No. 6,468,996 Substituted hetero-polycyclic compounds as PPAR? / PPAR? ...

139. US Pat. No. 6,432,996 Pharmaceutical composition

140. US Pat. No. 6,355,808 Benzimidazole compounds, their production and use

141. US Pat. No. 6,348,481 Pharmaceutical composition for angiotensin II-mediated

142. US Pat. No. 6,232,334 Benzimidazole derivatives, their production and use

143. US Pat. No. 6,228,874 Pharmaceutical composition for angiotensin II-mediated ...

144. US Pat. No. 6,100,252 Heterocyclic compounds and their use as angiotensin antagonists

145. US Pat. No. 5,958,961 Pharmaceutical composition for angiotensin II-mediated diseases

146. US Pat. No. 5,639,773 Hypotensive eyepiece agent

147. US Pat. No. 6,355,808 Benzimidazole compounds, their production and use

148. US Pat. No. 6,232,334 Benzimidazole derivatives, their production and use

149. US Pat. No. 5,463,073 Thienoimidazole derivatives, their production and use

150. US Pat. No. 5,401,764 Benzimidazole derivative compositions and medical use thereof

151. US Pat. No. 5,389,641 Fused heterocyclic compounds, having angiotensin II antagonistic activity

152. US Pat. No. 5,354,766 Compound and salts thereof which antagonize angiotensin II

153. US Pat. No. 5,328,919 Pivaloyloxymethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof ...

154. US Pat. No. 5,284,661 Fused thiophene derivatives, their production and use

155. US Pat. No. 5,250,554 Benzimidazole derivatives useful as angiotensin II inhibitors

156. US Pat. No. 5,243,054 Compound which is angiotensin II antagonist

157. US Pat. No. 5,196,444 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1 - [[2 '- (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylate ...

158. US Pat. No. 5,162,326 Pyrimidinedione derivatives, their production and use

159. US Pat. No. 5,128,356 Benzimidazole derivatives and their use

160. US Pat. No. 6,200,995 PPARγ modulators (Tularik)

161. US Prov. Pat. No. 60/283774 Optimized ligands for PPARs

162. US Prov. Pat. No. 60/189514 Novel Antioxidants

163. US Prov. Pat. No. 60 / 402,425 Identification and uses of novel PPAR ligands that do not cause Huid retention

The patents mentioned above contain the descriptions of compounds that can be used in the practice of this invention. Consequently, said compounds are protected by the claims of this invention.

All publications, patents and Patent publications mentioned in this application are incorporated into this application, by reference made in the request, in full and for any purpose.

Although the invention has been described with reference to preferred embodiments and examples thereof, the The scope of the present invention is not limited only to those embodiments described. As you will quickly notice experts in the art, adaptations and modifications to the invention described above without departing of the spirit and scope of the invention, which are defined and circumscribed in the claims that are added.

All of the above is basically offered with the objective to illustrate. Those skilled in the art will easily notice that the operating conditions, the materials, the steps procedural and other parameters of the invention described in the This application may also be modified or substituted for various ways without departing from the spirit and scope of the invention. For example, the invention has been described with patients. human as the usual receptor, but the use is also contemplated vet. Therefore, the above description of the invention It should not be considered as limiting but merely exemplary

Claims (23)

1. Use of a therapeutically effective amount of a compound sufficient to (a) at least partially activate receptors activated by perixosomal proliferators (PPARs) (b) at least partially inhibit, antagonize or bite a activity of angiotensin II type 1 receptors for preparation of a pharmaceutical composition for prophylactically prevent, delay or delay the development of a disorder inflammatory or metabolic selected from a group of diseases consisting of type 2 diabetes mellitus syndrome metabolic and inflammation caused by osteoarthritis in a mammal human or nonhuman 2. The use according to claim 1, wherein the Mammal is human. 3. The use according to claim 1, wherein the Mammal is not human. 4. Use according to any one of the claims 1 to 3, where prevention, procrastination or prophylactic delay in the development of inflammatory disorder or Metabolic does not cause, promote or aggravate fluid retention, peripheral edema, pulmonary edema or congestive heart failure in the mammal 5. Use according to any one of the claims 1 to 4, wherein said amount therapeutically effective is enough to prophylactically prevent, retard or delay the development of at least one disorder  or metabolic disease selected from a group consisting of insulin resistance, glucose intolerance, deficiency in glucose tolerance, deficiency in serum glucose in fasting, fasting blood glucose deficiency, hyperinsulinemia, prediabetes, type 1 diabetes, diabetes mellitus type 2, insulin resistant hypertension, metabolic syndrome, hypertensive metabolic syndrome, syndrome X (metabolic), syndrome dysmetabolic, obesity, visceral obesity, hypertriglyceridemia, high concentrations of serum free fatty acids, high concentrations of serum C-reactive protein, high concentrations of lipoproteins (a) in the serum, high concentrations of homocysteine in the serum, high concentrations of serum cholesterol produced by Low and low density lipoproteins (LDL) concentrations high serum LDL cholesterol, high concentrations in serum phospholipase associated with lipoproteins (A2), concentrations low cholesterol (HDL) in serum produced by lipoproteins high density, reduced concentrations of HDL cholesterol (2b) in the serum, and reduced concentrations of adiponectin in the serum. 6. Use according to any one of the claims 1 to 5, wherein said compound increases the activity of a subtype of PPAR, gamma PPAR or a heterodimer of X PPAR gamma retinoid receptor (PPARgamma-RXR). 7. Use according to any one of the claims 1 to 6, wherein the activity of the subtype of PPAR, PPAR gamma or the X PPAR retinoid receptor heterodimer gamma (PPARgamma-RXR) is increased in combination with an increase in the activity of at least one of the PPARalfa and PPARdelta. 8. Use according to any one of the claims 1 to 6, wherein said amount of the therapeutically effective compound is enough to prevent, slow down or prophylactically delay at least one disorder or metabolic disease selected from a group consisting of insulin resistance, glucose intolerance, deficiency in glucose tolerance, serum glucose deficiency in fasting, hyperinsulinemia, prediabetes, type 1 diabetes, diabetes Type 2 mellitus, insulin resistant hypertension, syndrome metabolic, hypertensive metabolic syndrome, syndrome X (metabolic), dysmetabolic syndrome, obesity, visceral obesity, hypertriglyceridemia, high concentrations of fatty acids serum free, high protein concentrations serum C reagent, high concentrations of lipoproteins (a) in serum, elevated homocysteine concentrations in the serum, high serum cholesterol levels produced by small and low density lipoproteins (LDL *), high concentrations of lipoprotein-associated phospholipase (A2), reduced serum cholesterol concentrations produced by high density lipoproteins (HDL *), concentrations low serum cholesterol produced by HDL (2b), and reduced concentrations of adiponectin in the serum. 9. Use according to any one of the claims 1 to 6, wherein the compound has the formula  General following: 24 In which R1 is a hydrocarbon residue optionally substituted, which is optionally linked to through a heteroatom; R2 is a heterocyclic residue of 5-7 optionally substituted members, which has, as a group capable of constituting a ring, a carbonyl group, a thiocarbonyl group, an optionally oxidized sulfur atom, or a group that can be transmuted into these; X is a direct link or a spacer that has an atomic length of two or less between the Y ring and W ring; W and Y independently are a residue of optionally substituted aromatic hydrocarbon containing a heteroatom or an optionally substituted heterocyclic residue; n it is an integer of 1 or 2; a and b that form the residue heterocyclic are independently one or two atoms of optionally substituted carbons or heteroatoms; c is an atom of carbons or an optionally substituted heteroatom; and in the group of formula: 25 the substituents of atoms adjacent that form the ring are optionally linked together to form a ring of 5 or 6 members together with the two atoms forming the ring or a salt thereof, pharmaceutically acceptable, or a pharmaceutically solvate thereof acceptable. 10. Use according to any one of the claims 1 to 9, wherein the compounds are formulated  For oral administration. 11. Use according to any one of the claims 1 to 9, wherein the compound is formulated for topical administration. 12. Use according to any one of the claims 1 to 10, wherein the compound is telmisartan,  or an analogue thereof. 13. The use according to claim 12, wherein the Total effective daily dose administered orally is selected between an approximate range of 20 mg to 1000 mg. 14. Use according to any one of the claims 1 to 10, wherein the compound is irbesartan, or an analogue thereof. 15. The use of claim 14, wherein the Total effective daily dose administered orally is selected between an approximate range of 20 mg to 1000 mg. 16. The use of claims 12 or 13, where the therapeutically effective amount of said telmisartan, or an analogue thereof, is sufficient to prevent, slow down or prophylactically delay the development of at least one disorder or metabolic disease selected from the group consisting of type 2 diabetes mellitus, metabolic syndrome and inflammation caused for osteoarthritis. 17. The use of claims 14 or 15, where the amount of therapeutically effective irbesartan, or a similar to it, it is enough: (a) to prevent, slow down or delay prophylactically the development of at least one disorder or metabolic disease selected from the group consisting of insulin resistance, glucose intolerance, deficiency in glucose tolerance, serum glucose deficiency in fasting, hyperinsulinemia, prediabetes, type 1 diabetes, diabetes type 2 mellitus, or (b) to prevent, slow down or delay prophylactically at least one metabolic disorder or disease selected from the group consisting of insulin hypertension resistant, metabolic syndrome, hypertensive metabolic syndrome, X syndrome (metabolic), dysmetabolic syndrome, obesity, obesity visceral, hypertriglyceridemia, high acid concentrations serum free fatty acids, high protein concentrations serum C reagent, high concentrations of lipoproteins (a) in serum, elevated serum homocysteine concentrations, high concentrations of serum cholesterol produced by Small low density lipoproteins (LDL) concentrations elevated phospholipase associated with lipoproteins (A2), reduced concentrations of serum cholesterol produced by high density lipoproteins (HDL), reduced concentrations in serum HDL cholesterol (2b), and reduced concentrations of serum adiponectin. 18. The use of claims 14 or 15, where the amount of therapeutically effective irbesartan, or a Its analogue is sufficient: (a) to prevent, slow down or delay prophylactically the development of diabetes mellitas; or (b) to prevent, slow down or delay prophylactically the development of a disease or disorder metabolic selected from a group consisting of prediabetes and metabolic syndrome 19. The use of claims 14 or 15, where the amount of therapeutically effective irbesartan, or a similar to it, it is enough to prevent, slow down or Prophylactically delay hypertriglyceridemia. 20. The use of claims 14 or 15, where the amount of therapeutically effective irbesartan, or a similar to it, it is enough to prevent, slow down or Prophylactically delay high LDL cholesterol levels. 21. A method of selecting compounds for Prophylactically prevent, slow down or delay the development of an inflammatory or metabolic disorder in a mammal, comprising The method of selecting a compound that is capable of: (a) at least partially activate the receivers activated by perixosomal proliferators (PPARs); Y (b) at least partially inhibit, antagonize or block an activity of angiotensin II type receptors one. 22. A method of selecting compounds for the preparation of a pharmaceutical composition for Prophylactically prevent, slow down or delay the development of an inflammatory or metabolic disorder in a non-human mammal, the method comprising selecting a compound that is capable from: (a) at least partially activate the receivers activated by perixosomal proliferators (PPARs); Y (b) at least partially inhibit, antagonize or block an activity of angiotensin II type receptors one. 23. The method of claims 21 or 22 which further comprises the selection of a compound that does not cause, promotes or aggravates at least one of the following conditions: fluid retention, pulmonary edema or heart failure congestive in the mammal.